KR20010112393A - C7 Heterosubstituted Acetate Taxanes as Antitumor Agents - Google Patents
C7 Heterosubstituted Acetate Taxanes as Antitumor Agents Download PDFInfo
- Publication number
- KR20010112393A KR20010112393A KR1020017012589A KR20017012589A KR20010112393A KR 20010112393 A KR20010112393 A KR 20010112393A KR 1020017012589 A KR1020017012589 A KR 1020017012589A KR 20017012589 A KR20017012589 A KR 20017012589A KR 20010112393 A KR20010112393 A KR 20010112393A
- Authority
- KR
- South Korea
- Prior art keywords
- pyridyl
- taxane
- thienyl
- furyl
- phenyl
- Prior art date
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- 229940123237 Taxane Drugs 0.000 title claims abstract description 101
- 150000001242 acetic acid derivatives Chemical class 0.000 title claims description 4
- 239000002246 antineoplastic agent Substances 0.000 title description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
- 150000001875 compounds Chemical class 0.000 claims description 91
- -1 phenyl Taxane Chemical class 0.000 claims description 83
- 125000000217 alkyl group Chemical group 0.000 claims description 82
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 48
- 125000002541 furyl group Chemical group 0.000 claims description 46
- 125000001544 thienyl group Chemical group 0.000 claims description 45
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 125000004076 pyridyl group Chemical group 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 36
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- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 25
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- 230000002401 inhibitory effect Effects 0.000 claims description 5
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
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- 230000004962 physiological condition Effects 0.000 description 1
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- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001522 polyglycol ester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- 150000003254 radicals Chemical class 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SCEZSEOTDXHAOD-UHFFFAOYSA-N tris(2,3-dihydroxypropyl) 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound OCC(O)COC(=O)CC(O)(C(=O)OCC(O)CO)CC(=O)OCC(O)CO SCEZSEOTDXHAOD-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
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- 235000019386 wax ester Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000010698 whale oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
본 발명은 C(7)에 헤테로치환된 아세테이트 치환체, C(10)에 히드록시 치환체 및 소정 범위의 C(2), C(9), C(14) 및 측쇄 치환체를 갖는 탁산에 관한 것이다.The present invention relates to taxanes having a heterosubstituted acetate substituent on C (7), a hydroxy substituent on C (10) and a range of C (2), C (9), C (14) and side chain substituents.
Description
박카틴(baccatin) Ⅲ 및 탁솔을 비롯한 테르펜의 탁산류 화합물은 생물학 및 화학 분야에서 상당한 관심의 대상이었다. 탁솔은 그 자체로 암에 대한 화학요법제로서 사용되며, 넓은 범위의 종양 억제 활성을 가지고 있다. 탁솔은 2'R, 3'S 배위를 가지고 있으며, 그 구조식은 하기와 같다:Taxane compounds of terpenes, including baccatin III and taxol, have been of considerable interest in the biology and chemistry fields. Taxol is itself used as a chemotherapeutic agent for cancer and has a wide range of tumor suppressor activity. Taxol has a 2'R, 3'S configuration, and the structural formula is:
상기 식에서, Ac는 아세틸이다.Wherein Ac is acetyl.
콜린(Colin) 등은 미국 특허 제4,814,470호에서 특정 탁솔 유사체가 탁솔보다 상당히 높은 활성을 갖는다고 보고하였다. 이러한 유사체들 중의 하나인, 통상도세탁셀(docetaxel)이라 불리우는 화합물은 하기의 구조식을 갖는다:Colin et al. Reported in US Pat. No. 4,814,470 that certain taxol analogs have significantly higher activity than taxol. One of these analogs, a compound called docetaxel, has the following structural formula:
탁솔과 도세탁셀도 화학요법제로서 유용하긴 하지만, 다양한 양으로 투여되는 경우에 특정 유형의 암에 대해서는 효능이 제한적이고 환자에 대해 독성이 있는 등 효과 면에서 한계가 있다. 따라서, 효능이 향상되고 독성이 감소된 또다른 화학요법제에 대한 요구가 남아있는 실정이다.Taxol and docetaxel are useful as chemotherapeutic agents, but when administered in varying amounts, there are limitations in terms of effectiveness, such as limited efficacy for certain types of cancer and toxicity to patients. Thus, there remains a need for another chemotherapeutic agent with improved efficacy and reduced toxicity.
<발명의 요약>Summary of the Invention
따라서, 본 발명의 목적은 항종양제로서의 효능 및 독성 면에서 탁솔 및 도세탁셀에 필적하는 탁산을 제공하는 것이다. 대체적으로, 이들 탁산은 C-7 위치에 헤테로치환된 아세테이트 치환체, C-10 위치에 히드록시 치환체, 그리고 소정 범위의 C-3' 치환체를 갖는다.Accordingly, it is an object of the present invention to provide taxanes comparable to Taxol and docetaxel in terms of efficacy and toxicity as antitumor agents. Generally, these taxanes have an acetate substituent heterosubstituted at the C-7 position, a hydroxy substituent at the C-10 position, and a range of C-3 'substituents.
따라서, 간략히 설명하면, 본 발명은 탁산 화합물 그 자체, 탁산 및 제약상 허용되는 담체를 포함하는 제약 조성물, 및 그 투여 방법에 관한 것이다.Thus, briefly described, the present invention relates to pharmaceutical compositions comprising the taxane compound itself, taxanes and pharmaceutically acceptable carriers, and methods of administration thereof.
본 발명의 다른 목적 및 특징 중 일부는 자명할 것이고, 일부는 본 명세서의 이하에 지적될 것이다.Some of the other objects and features of the present invention will be apparent, and some will be pointed out below in this specification.
본 발명은 항종양제로서의 예상치 못한 유용성을 지닌 신규 탁산에 관한 것이다.The present invention relates to novel taxanes with unexpected utility as antitumor agents.
본 발명의 한 실시양태에서, 본 발명의 탁산은 하기 화학식 1의 구조에 상응한다.In one embodiment of the invention, the taxanes of the invention correspond to the structure of formula (I).
상기 식에서,Where
R2는 아실옥시이고,R 2 is acyloxy,
R7은 헤테로치환된 아세테이트이고,R 7 is heterosubstituted acetate,
R9는 케토, 히드록시 또는 아실옥시이고,R 9 is keto, hydroxy or acyloxy,
R10은 히드록시이고,R 10 is hydroxy,
R14는 히드리도 또는 히드록시이고,R 14 is hydrido or hydroxy,
X3는 치환된 또는 비치환된 알킬, 알케닐, 알키닐, 페닐 또는 헤테로시클로이고,X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo,
X5는 -COX10, -COOX10또는 -CONHX10이고, 여기서 X10은 히드로카르빌, 치환된 히드로카르빌 또는 헤테로시클로이고,X 5 is -COX 10 , -COOX 10 or -CONHX 10 , wherein X 10 is hydrocarbyl, substituted hydrocarbyl or heterocyclo,
Ac는 아세틸이며,Ac is acetyl,
R7, R9및 R10은 독립적으로 알파 또는 베타 입체이성질체 배위를 갖는다.R 7 , R 9 and R 10 independently have alpha or beta stereoisomer configuration.
한 실시양태에서, R2는 에스테르(R2aC(O)O-), 카르바메이트(R2aR2bNC(O)O-), 카르보네이트(R2aOC(O)O-) 또는 티오카르바메이트(R2aSC(O)O-)이며, 여기서 R2a및 R2b는 독립적으로, 수소, 히드로카르빌, 치환된 히드로카르빌 또는 헤테로시클로이다. 바람직한 실시양태에서, R2는 에스테르(R2aC(O)O-)이며, 여기서 R2a는 아릴 또는 헤테로방향족 기이다. 다른 바람직한 실시양태에서, R2는 에스테르(R2aC(O)O-)이며, 여기서 R2a는 치환된 또는 비치환된 페닐, 푸릴, 티에닐 또는 피리딜이다. 특히 바람직한 한 실시양태에서, R2는 벤조일옥시이다.In one embodiment, R 2 is an ester (R 2a C (O) O—), carbamate (R 2a R 2b NC (O) O—), carbonate (R 2a OC (O) O—) or Thiocarbamate (R 2a SC (O) O—), wherein R 2a and R 2b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R 2 is an ester (R 2a C (O) O—), wherein R 2a is an aryl or heteroaromatic group. In another preferred embodiment, R 2 is an ester (R 2a C (O) O—), wherein R 2a is substituted or unsubstituted phenyl, furyl, thienyl or pyridyl. In one particularly preferred embodiment, R 2 is benzoyloxy.
한 실시양태에서, R7은 R7aC(O)O-이며, 여기서 R7a는 헤테로치환된 메틸로서, 이 헤테로치환된 메틸 잔기는 R7a를 치환체로 갖는 탄소에 대해 베타 위치에 있는 탄소를 함유하지 않는다. 헤테로치환된 메틸은 1개 이상의 헤테로원자(예를 들어, 질소, 산소, 규소, 인, 붕소, 황 또는 할로겐 원자임) 및 임의로는 수소와 공유결합되어 있다. 또한, 헤테로원자는 다른 원자로 치환되어 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 옥시, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 또는 에테르 잔기를 형성할 수 있다. R7치환체의 예로는 R7aCOO-가 있으며, 여기서 R7a는 클로로메틸, 히드록시메틸, 메톡시메틸, 에톡시메틸 또는 메틸티오메틸이다.In one embodiment, R 7 is R 7a C (O) O—, wherein R 7a is heterosubstituted methyl, wherein the heterosubstituted methyl moiety represents a carbon at a beta position relative to the carbon having R 7a as a substituent. It does not contain. Heterosubstituted methyl is covalently bonded with one or more heteroatoms (eg, nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms) and optionally hydrogen. In addition, heteroatoms are substituted with other atoms such as heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester Or ether residues. Examples of R 7 substituents are R 7a COO—, where R 7a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl or methylthiomethyl.
본 발명의 한 실시양태에서는 R9가 케토이지만, 다른 실시양태에서는 R9가 알파 또는 베타 입체이성질체 배위를 가질 수 있으며(베타 입체이성질체 배위가 바람직함), 예를 들면 α- 또는 β-히드록시 또는 α- 또는 β-아실옥시일 수 있다. 예를 들어, R9가 아실옥시일 때, 이는 에스테르(R9aC(O)O-), 카르바메이트(R9aR9bNC(O)O-), 카르보네이트(R9aOC(O)O-) 또는 티오카르바메이트(R9aSC(O)O-)이며, 여기서 R9a및 R9b는 독립적으로 수소, 히드로카르빌, 치환된 히드로카르빌 또는 헤테로시클로이다. R9가 에스테르 (R9aC(O)O-)인 경우, R9a는 비치환된 알킬, 비치환된 알케닐, 비치환된 아릴 또는 비치환된 헤테로방향족 기이다. 더욱 바람직하게는, R9가 에스테르(R9aC(O)O-)이며, 여기서 R9a는 치환된 또는 비치환된 페닐, 비치환된 푸릴, 비치환된 티에닐 또는 비치환된 피리딜이다. 한 실시양태에서, R9는 (R9aC(O)O-)이며, 여기서 R9a는 메틸, 에틸, 프로필(직쇄, 분지쇄 또는 시클릭), 부틸(직쇄, 분지쇄 또는 시클릭), 펜틸(직쇄, 분지쇄 또는 시클릭) 또는 헥실(직쇄, 분지쇄 또는 시클릭)이다. 또다른 실시양태에서, R9는 (R9aC(O)O-)이며, 여기서 R9a는 치환된 메틸, 치환된 에틸, 치환된 프로필(직쇄, 분지쇄 또는 시클릭), 치환된 부틸(직쇄, 분지쇄 또는 시클릭), 치환된 펜틸(직쇄, 분지쇄 또는 시클릭) 또는 치환된 헥실(직쇄, 분지쇄 또는 시클릭)이며, 이 때 치환체(들)은 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 케토, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 및 에테르 잔기로 구성된 군으로부터 선택되지만, 인 함유 잔기는 아니다.In one embodiment of the invention R 9 is a keto, while in other embodiments R 9 may have an alpha or beta stereoisomeric configuration (a beta stereoisomeric configuration is preferred), for example α- or β-hydroxy Or α- or β-acyloxy. For example, when R 9 is acyloxy, it is an ester (R 9a C (O) O-), carbamate (R 9a R 9b NC (O) O-), carbonate (R 9a OC (O ) O-) or thiocarbamate (R 9a SC (O) O-), wherein R 9a and R 9b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. When R 9 is an ester (R 9a C (O) O—), R 9a is unsubstituted alkyl, unsubstituted alkenyl, unsubstituted aryl or unsubstituted heteroaromatic group. More preferably, R 9 is an ester (R 9a C (O) O—) wherein R 9a is substituted or unsubstituted phenyl, unsubstituted furyl, unsubstituted thienyl or unsubstituted pyridyl . In one embodiment, R 9 is (R 9a C (O) O—) wherein R 9a is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), Pentyl (straight, branched or cyclic) or hexyl (straight, branched or cyclic). In another embodiment, R 9 is (R 9a C (O) O—) wherein R 9a is substituted methyl, substituted ethyl, substituted propyl (straight, branched or cyclic), substituted butyl ( Straight, branched or cyclic), substituted pentyl (straight, branched or cyclic) or substituted hexyl (straight, branched or cyclic), wherein the substituent (s) are heterocyclo, alkoxy, alkenoxy , Alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether residues, but not phosphorus containing residues.
X3치환체의 예로는 치환된 또는 비치환된 C2내지 C8알킬, 치환된 또는 비치환된 C2내지 C8알케닐, 치환된 또는 비치환된 C2내지 C8알키닐, 5 또는 6원 고리 원자를 함유하는 치환된 또는 비치환된 헤테로방향족 기, 및 치환된 또는 비치환된 페닐이 있다. X3치환체의 바람직한 예로는 치환된 또는 비치환된 에틸, 프로필, 부틸, 시클로프로필, 시클로부틸, 시클로헥실, 이소부테닐, 푸릴, 티에닐 및 피리딜이 있다.Examples of X 3 substituents include substituted or unsubstituted C 2 to C 8 alkyl, substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 to C 8 alkynyl, 5 or 6 Substituted or unsubstituted heteroaromatic groups containing a ring member, and substituted or unsubstituted phenyl. Preferred examples of X 3 substituents are substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl and pyridyl.
X5치환체의 예로는 -COX10, -COOX10또는 -CONHX10이 있으며, 여기서 X10은 치환된 또는 비치환된 알킬, 알케닐, 페닐 또는 헤테로방향족 기이다. X5치환체의 바람직한 예로는 -COX10, -COOX10또는 -CONHX10이 있으며, 여기서 X10은 (i) 치환된 또는 비치환된 메틸, 에틸, 프로필(직쇄, 분지쇄 또는 시클릭), 부틸(직쇄, 분지쇄 또는 시클릭), 펜틸(직쇄, 분지쇄 또는 시클릭) 또는 헥실(직쇄, 분지쇄 또는 시클릭)과 같은 치환된 또는 비치환된 C1내지 C8알킬, (ii) 치환된 또는 비치환된 에테닐, 프로페닐(직쇄, 분지쇄 또는 시클릭), 부테닐(직쇄, 분지쇄 또는 시클릭), 펜테닐(직쇄, 분지쇄 또는 시클릭) 또는 헥세닐(직쇄, 분지쇄 또는 시클릭)과 같은 치환된 또는 비치환된 C2내지 C8알케닐, (iii) 치환된 또는 비치환된 에티닐, 프로피닐(직쇄 또는 분지쇄), 부티닐(직쇄 또는 분지쇄), 펜티닐(직쇄 또는 분지쇄)또는 헥시닐(직쇄 또는 분지쇄)과 같은 치환된 또는 비치환된 C2내지 C8알키닐, (iv) 치환된 또는 비치환된 페닐, 또는 (v) 푸릴, 티에닐 또는 피리딜과 같은 치환된 또는 비치환된 헤테로방향족 기이며, 이 때 치환체(들)은 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 케토, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 및 에테르 잔기로 구성된 군으로부터 선택되지만, 인 함유 잔기는 아니다.Examples of X 5 substituents are —COX 10 , —COOX 10 or —CONHX 10 , wherein X 10 is a substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic group. Preferred examples of X 5 substituents include -COX 10 , -COOX 10 or -CONHX 10 , wherein X 10 is (i) substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl Substituted or unsubstituted C 1 to C 8 alkyl, such as (linear, branched or cyclic), pentyl (straight, branched or cyclic) or hexyl (straight, branched or cyclic), (ii) substitution Or unsubstituted ethenyl, propenyl (straight, branched or cyclic), butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched) Substituted or unsubstituted C 2 to C 8 alkenyl, such as chain or cyclic), (iii) substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched) Substituted or unsubstituted C 2 to C 8 alkynyl, such as pentynyl (straight or branched) or hexynyl (straight or branched), (iv) substituted or Unsubstituted phenyl or (v) substituted or unsubstituted heteroaromatic groups, such as furyl, thienyl or pyridyl, wherein the substituent (s) are heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, Hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether residues, but not phosphorus containing residues.
본 발명의 한 실시양태에서, 탁산은 X5가 -COX10(여기서, X10은 페닐임) 또는 -COOX10(여기서, X10은 t-부톡시카르보닐임)이고, R7이 R7aC(O)O-이며, 여기서 R7a는 알콕시메틸, 바람직하게는 메톡시메틸 또는 에톡시메틸인 화학식 1의 구조에 상응한다. 본 발명의 다른 실시양태에서, 탁산은 X5가 -COX10(여기서, X10은 페닐임) 또는 -COOX10(여기서, X10은 t-부톡시카르보닐임)이고, R7이 R7aC(O)O-이며, 여기서 R7a는 아실옥시메틸, 바람직하게는 아세톡시메틸인 화학식 1의 구조에 상응한다.In one embodiment of the invention, the taxane is X 5 is -COX 10 (wherein X 10 is phenyl) or -COOX 10 (wherein X 10 is t-butoxycarbonyl) and R 7 is R 7a C (O) O—, where R 7a corresponds to the structure of formula (1) which is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the invention, the taxane is X 5 is -COX 10 (where X 10 is phenyl) or -COOX 10 (where X 10 is t-butoxycarbonyl) and R 7 is R 7a C (O) O—, where R 7a corresponds to the structure of Formula 1 which is acyloxymethyl, preferably acetoxymethyl.
본 발명의 다른 실시양태에서, 탁산은 X5가 -COX10(여기서, X10은 페닐임) 또는 -COOX10(여기서, X10은 t-부톡시카르보닐임)이고, R7이 R7aC(O)O-이며, 여기서 R7a는 메톡시메틸 또는 에톡시메틸과 같은 알콕시메틸, 또는 페녹시메틸과 같은 아릴옥시메틸이고, X3이 헤테로시클로인 화학식 1의 구조에 상응한다. 본 발명의 다른 실시양태에서, 탁산은 X5가 -COX10(여기서, X10은 페닐임) 또는 -COOX10(여기서, X10은 t-부톡시카르보닐임)이고, R7이 R7aC(O)O-이며, 여기서 R7a는 아실옥시메틸, 바람직하게는 아세톡시메틸이고, X3이 헤테로시클로인 화학식 1의 구조에 상응한다.In another embodiment of the invention, the taxane is X 5 is -COX 10 (where X 10 is phenyl) or -COOX 10 (where X 10 is t-butoxycarbonyl) and R 7 is R 7a C (O) O—, where R 7a corresponds to the structure of formula (I) in which alkoxymethyl, such as methoxymethyl or ethoxymethyl, or aryloxymethyl, such as phenoxymethyl, and X 3 is heterocyclo. In another embodiment of the invention, the taxane is X 5 is -COX 10 (where X 10 is phenyl) or -COOX 10 (where X 10 is t-butoxycarbonyl) and R 7 is R 7a C (O) O—, where R 7a corresponds to the structure of formula (I) wherein acyloxymethyl, preferably acetoxymethyl and X 3 is heterocyclo.
바람직한 한 실시양태에서, 본 발명의 탁산은 하기 화학식 2의 구조에 상응한다.In one preferred embodiment, the taxanes of the invention correspond to the structure of formula (2).
상기 식에서,Where
R7은 헤테로치환된 아세테이트이고,R 7 is heterosubstituted acetate,
R10은 히드록시이고,R 10 is hydroxy,
X3는 치환된 또는 비치환된 알킬, 알케닐, 알키닐 또는 헤테로시클로이고,X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl or heterocyclo,
X5는 -COX10, -COOX10또는 -CONHX10이고, 여기서 X10은 히드로카르빌, 치환된 히드로카르빌 또는 헤테로시클로이다.X 5 is —COX 10 , —COOX 10 or —CONHX 10 , wherein X 10 is hydrocarbyl, substituted hydrocarbyl or heterocyclo.
예를 들어, 탁산이 화학식 2의 구조에 상응하는 바람직한 실시양태에서, R7은 R7aCOO-일 수 있으며, 여기서 R7a는 헤테로치환된 메틸, 더욱 바람직하게는 헤테로치환체가 질소, 산소, 규소, 인, 붕소, 황 또는 할로겐 원자로 구성된 군에서 선택되는 헤테로치환된 메틸, 더더욱 바람직하게는 헤테로치환체가 알콕시 또는 아실옥시인 헤테로치환된 메틸이다. R7a가 상기 기 중에서 선택되는 한편, 한 실시양태에서는 X3가 치환된 또는 비치환된 알킬, 알케닐, 페닐 또는 헤테로시클로로부터 선택되고, 더욱 바람직하게는 치환된 또는 비치환된 알케닐, 페닐 또는 헤테로시클로로부터 선택되며, 더더욱 바람직하게는 치환된 또는 비치환된 페닐 또는 헤테로시클로로부터 선택되고, 가장 바람직하게는 푸릴, 티에닐 또는 피리딜과 같은 헤테로시클로이다. R7a및 X3가 상기 기 중에서 선택되는 한편, 한 실시양태에서는 X5가 -COX10(여기서, X10은 페닐, 알킬 또는 헤테로시클로, 더욱 바람직하게는 페닐임)이다. 또는, R7a및 X3가 상기 기 중에서 선택되는 한편, 한 실시양태에서는 X5가 -COX10(여기서, X10은 페닐, 알킬 또는 헤테로시클로, 더욱 바람직하게는 페닐임) 또는 -COOX10(여기서, X10은 알킬, 바람직하게는 t-부틸임)이다. 따라서, 더욱 바람직한 실시양태에서 탁산은 (i) X5가 -COOX10(여기서, X10은 tert-부틸임) 또는 -COX10(여기서, X10은 페닐임)이고, (ii) X3가 치환된 또는 비치환된 시클로알킬, 알케닐, 페닐 또는 헤테로시클로, 더욱 바람직하게는 치환된 또는 비치환된 이소부테닐, 페닐, 푸릴, 티에닐 또는 피리딜, 더더욱 바람직하게는 비치환된 이소부테닐, 푸릴, 티에닐 또는 피리딜이며, (iii) R7a가 알콕시아세틸 또는 아실옥시아세틸인 화학식 2의 구조에 상응한다.For example, in a preferred embodiment wherein taxane corresponds to the structure of Formula 2, R 7 may be R 7a COO—, wherein R 7a is heterosubstituted methyl, more preferably heterosubstituted with nitrogen, oxygen, silicon , Heterosubstituted methyl selected from the group consisting of phosphorus, boron, sulfur or halogen atoms, even more preferably heterosubstituted methyl wherein the heterosubstituent is alkoxy or acyloxy. While R 7a is selected from the above groups, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl Or heterocyclo, even more preferably selected from substituted or unsubstituted phenyl or heterocyclo, most preferably heterocyclo such as furyl, thienyl or pyridyl. While R 7a and X 3 are selected from the above groups, in one embodiment X 5 is —COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Or, R 7a and X 3 are selected from the above groups, while in one embodiment X 5 is —COX 10 (wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl) or —COOX 10 ( X 10 is alkyl, preferably t-butyl. Thus, in a more preferred embodiment the taxane is (i) X 5 is -COOX 10 where X 10 is tert-butyl or -COX 10 where X 10 is phenyl, and (ii) X 3 is Substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl or pyridyl, even more preferably unsubstituted isobutenyl, Corresponding to the structure of formula (2) wherein furyl, thienyl or pyridyl and (iii) R 7a is alkoxyacetyl or acyloxyacetyl.
일반 화학식 1의 탁산은 β-락탐을 탁산 테트라시클릭 핵 및 C-13 금속성 산화물 치환체를 갖는 알콕시드로 처리하여 C-13에 β-아미도 에스테르 치환체를 갖는 화합물(홀튼(Holton)의 미국 특허 제5,466,834호에 더 자세히 기재됨)을 생성한 후, 히드록시 보호기를 제거함으로써 수득할 수 있다. 상기 β-락탐은 하기 화학식 3의 구조를 가지며, 상기 알콕시드는 하기 화학식 4의 구조를 갖는다.Taxanes of general formula (1) are treated with β-lactams with alkoxides having a taxane tetracyclic nucleus and C-13 metallic oxide substituents to give compounds having β-amido ester substituents at C-13 (Holton, U.S. Pat. 5,466,834), which can be obtained by removing hydroxy protecting groups. The β-lactam has a structure of Formula 3, and the alkoxide has a structure of Formula 4.
상기 식에서, P2는 히드록시 보호기이고, X3및 X5는 상기 정의한 바와 같다.Wherein P 2 is a hydroxy protecting group and X 3 and X 5 are as defined above.
상기 식에서, M은 금속 또는 암모늄이고, P10은 히드록시 보호기이며, R7은 상기 정의한 바와 같다.Wherein M is a metal or ammonium, P 10 is a hydroxy protecting group and R 7 is as defined above.
상기 알콕시드는 10-데아세틸박카틴 Ⅲ으로부터 C-10 히드록실기의 선택적인 보호 이후에 C-7 히드록실기를 에스테르화시키고(홀튼 등의 PCT 특허 출원 WO 제99/09021호에 더 자세히 기재됨), 금속성 아미드로 처리함으로써 제조될 수 있다.The alkoxides esterify C-7 hydroxyl groups after selective protection of C-10 hydroxyl groups from 10-deacetylbaccatin III (described in more detail in PCT patent application WO 99/09021 to Holton et al.). Can be prepared by treating with a metallic amide.
C(2), C(9) 및 C(14)에 대안적인 치환체를 갖는 10-데아세틸박카틴 Ⅲ의 유도체, 및 이들의 제조 방법은 당업계에 공지되어 있다. C(2)에 벤조일옥시가 아닌 아실옥시 치환체를 갖는 탁산 유도체는, 예를 들어 홀튼 등의 미국 특허 제5,728,725호 또는 킹스톤(Kingston) 등의 미국 특허 제6,002,023호에 기재된 바와 같이 제조될 수 있다. C(9)에 케토 대신에 아실옥시 또는 히드록시 치환체를 갖는 탁산은, 예를 들어 홀튼 등의 미국 특허 제6,011,056호 또는 구나워다나(Gunawardana) 등의 미국 특허 제5,352,806호에 기재된 바와 같이 제조될 수 있다. C(14)에 베타 히드록시 치환체를 갖는 탁산은 자연 발생의 14-히드록시-10-데아세틸박카틴 Ⅲ으로부터 제조될 수 있다.Derivatives of 10-deacetylbaccatin III having alternative substituents to C (2), C (9) and C (14), and methods for their preparation are known in the art. Taxane derivatives having an acyloxy substituent other than benzoyloxy in C (2) can be prepared, for example, as described in US Pat. No. 5,728,725 to Holton et al. Or US Pat. No. 6,002,023 to Kingston et al. Taxanes having acyloxy or hydroxy substituents in place of keto in C (9) may be prepared, for example, as described in US Pat. No. 6,011,056 to Holton et al. Or US Pat. No. 5,352,806 to Gunawardana et al. Can be. Taxanes with beta hydroxy substituents on C (14) can be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.
β-락탐 출발 물질의 제조 및 분리 방법은 통상적으로 잘 공지되어 있다. 예를 들어, β-락탐은 홀튼의 미국 특허 제5,430,160호에 기재된 바와 같이 제조될 수 있으며, 생성된 β-락탐의 거울이성질체 혼합물은 리파아제, 효소(예를 들어, 파텔(Patel)의 미국 특허 제5,879,929호 및 파텔의 미국 특허 제5,567,614호에 기재됨), 또는 간 균질화물(예를 들어, PCT 특허 출원 제00/41204호에 기재됨)을 이용하는 입체선택적 가수분해에 의해 분리될 수 있다. β-락탐이 C(4) 위치에서 푸릴로 치환된 바람직한 실시양태에서, β-락탐은 하기의 반응식에 예시된 바와 같이제조될 수 있다:Processes for the preparation and separation of β-lactam starting materials are usually well known. For example, β-lactam can be prepared as described in Holton's US Pat. No. 5,430,160, and the enantiomeric mixture of the resulting β-lactam is a lipase, an enzyme (e.g. Patel's U.S. Pat. 5,879,929 and Patel's US Pat. No. 5,567,614), or by stereoselective hydrolysis using liver homogenates (e.g., described in PCT Patent Application 00/41204). In a preferred embodiment wherein β-lactam is substituted with furyl at position C (4), β-lactam may be prepared as illustrated in the following scheme:
상기 식에서, Ac는 아세틸이고, NEt3는 트리에틸아민이고, CAN은 세릭 암모늄 질산염이며, p-TsOH는 p-톨루엔술폰산이다.Wherein Ac is acetyl, NEt 3 is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid.
소의 간을 이용한 분리는, 예를 들어 β-락탐의 거울이성질체 혼합물을 소 간의 현탁액(20g의 동결된 소 간을 블렌더에 가한 후, pH 8의 완충액을 가하여 총 부피를 1 ℓ로 함으로써 제조됨)과 혼합함으로써 수행될 수 있다.Separation using bovine liver is prepared, for example, by suspension of bovine liver enantiomer mixture of β-lactam (20 g of frozen bovine liver is added to the blender, followed by pH 8 buffer to 1 L total volume). It can be carried out by mixing with.
본 발명의 화학식 1 화합물은 인간을 비롯한 포유동물에서 종양의 증식을 억제하는데 유용하며, 바람직하게는 본 발명의 화합물 항종양 유효량을 제약상 또는 약리학상 허용되는 1종 이상의 담체와 배합된 상태로 포함하는 제약 조성물의 형태로 투여된다. 당업계에 부형제, 비히클, 보조제, 보강제 또는 희석제로도 공지된상기 담체는 제약상 불활성인 임의의 물질이고, 조성물에 적합한 밀도 및 형태를 부여하며, 항종양성 화합물의 치료 효능을 감소시키지 않아야 한다. 상기 담체는 포유동물 또는 인간에게 적합하게 투여되었을 때 부반응, 알레르기성 반응 또는 기타 부적절한 반응이 일어나지 않는다면, 이는 "제약상 또는 약리학상 허용되는" 것이다.Formula 1 compounds of the present invention are useful for inhibiting the proliferation of tumors in mammals, including humans, and preferably comprise an anti-tumorally effective amount of a compound of the present invention in combination with one or more pharmaceutically or pharmaceutically acceptable carriers. In the form of a pharmaceutical composition. The carrier, also known in the art as an excipient, vehicle, adjuvant, adjuvant or diluent, is any pharmaceutically inert material, imparts suitable density and form to the composition and should not reduce the therapeutic efficacy of the antitumor compound. Such carriers are “pharmaceutically or pharmacologically acceptable” if no side reactions, allergic reactions or other inappropriate reactions occur when administered to a mammal or human.
본 발명의 항종양 화합물을 함유하는 제약 조성물은 종래의 어떠한 방식으로든 제제화될 수 있다. 적합한 제형은 선택된 투여 경로에 따라 달라질 것이다. 본 발명의 조성물은 투여 경로를 통해 표적 조직에 약물이 전달될 수만 있다면, 어떠한 투여 경로에도 적합하게 제제화될 수 있다. 적합한 투여 경로에는 경구 투여, 비경구 투여(예를 들면, 정맥내, 동맥내, 피하, 직장, 근육내, 안와내, 포낭내, 척수내, 복강내 또는 흉골내 투여), 국소 투여(비강, 경피, 안내 투여), 방광내 투여, 경막내 투여, 소화관내 투여, 폐 투여, 림프관내 투여, 강내 투여, 질 투여, 경요도 투여, 피부내 투여, 귀 투여, 유방내 투여, 구강 투여, 동소(orthotopic) 투여, 기관내 투여, 병변내 투여, 경피성 투여, 내시경적 투여, 경점막 투여, 설하 투여 및 장 투여가 포함되지만, 이에 제한되지는 않는다.Pharmaceutical compositions containing an antitumor compound of the invention may be formulated in any manner conventional. Proper formulation will depend upon the route of administration chosen. The composition of the present invention may be suitably formulated for any route of administration so long as the drug can be delivered to the target tissue via the route of administration. Suitable routes of administration include oral administration, parenteral administration (e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, orbital, intravesicular, intraspinal, intraperitoneal or intrasternal), topical administration (nasal, Transdermal, intraocular administration, intradural, intradural, digestive, lung, lymphatic, intraluminal, vaginal, transuretic, intradermal, ear, intramammary, oral, orthotopic orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual and enteral administration.
본 발명의 조성물에 사용하기 위한 제약상 허용되는 담체는 당업자에게 잘 공지되어 있으며, 사용되는 특정 항종양 화합물의 종류 및 그의 농도, 안정성 및 의도된 생체이용율; 이 조성물로 치료될 질환, 장애 또는 증상; 환자, 그의 연령, 체중 및 전신상태; 및 투여 경로를 비롯한 많은 인자에 기초하여 선택된다. 적합한 담체는 당업자에 의해 쉽게 결정될 수 있다 (그 내용이 본 명세서에 참고문헌으로 포함되는 문헌[J. G. Nairn, Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517] 참조).Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those skilled in the art and include the type of specific antitumor compound used and its concentration, stability and intended bioavailability; The disease, disorder or condition to be treated with this composition; The patient, his age, weight and general condition; And many factors including the route of administration. Suitable carriers can be readily determined by one skilled in the art (JG Nairn, Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (Incorporated herein by reference). 1985), pp. 1492-1517).
조성물은, 바람직하게는 정제, 분산가능한 분말제, 알약, 캡슐, 겔캡(gelcap), 캐플릿(caplet), 겔, 리포솜, 과립제, 용액제, 현탁제, 유제, 시럽, 엘릭실제, 트로키제, 당의정, 로젠지 또는 임의의 기타 경구 투여 형태로서 제제화된다. 본 발명에 유용한 경구 투여 형태를 제조하기 위한 기술 및 그 조성은 참고문헌[7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979; Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); 및 Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976)]에 기재되어 있다.The compositions are preferably tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, Formulated as dragees, lozenges or any other oral dosage form. Techniques for the preparation of oral dosage forms useful in the present invention and their compositions are described in 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979; Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); And Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).
본 발명의 경구 투여용 조성물은 제약상 허용되는 담체 중에 항종양 유효량의 본 발명의 화합물을 포함한다. 고형 투여 형태에 적합한 담체에는 당, 전분, 및 락토스, 활석, 수크로스, 젤라틴, 카르복시메틸셀룰로스, 한천, 만니톨, 소르비톨, 인산칼슘, 탄산칼슘, 탄산나트륨, 카올린, 알긴산, 아카시아, 옥수수 전분, 감자 전분, 나트륨 사카린, 탄산마그네슘, 트라가칸트(tragacanth), 미정질 셀룰로스, 콜로이드성 이산화규소, 크로스카르멜로스 나트륨, 스테아르산 마그네슘 및 스테아르산을 비롯한 기타 종래의 물질이 포함된다. 또한, 그러한 고형 투여 형태는 코팅되지 않거나, 또는 붕해 및 흡수 등을 지연시키기 위해 공지된 기술로 코팅될 수 있다.Compositions for oral administration of the present invention comprise an antitumorally effective amount of a compound of the present invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch. Other conventional materials, including sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and stearic acid. In addition, such solid dosage forms may be uncoated or coated by known techniques to delay disintegration, absorption, and the like.
또한, 본 발명의 항종양 화합물은 바람직하게는 비경구 투여용으로, 예를 들면 정맥내, 동맥내, 피하, 직장, 근육내, 안와내, 포낭내, 척수내, 복강내 또는 흉골내 경로를 통한 주사용으로 제제화된다. 본 발명의 비경구 투여용 조성물은 제약상 허용되는 담체 중에 항종양 유효량의 화합물을 포함한다. 비경구 투여에 적합한 투여 형태에는 용액제, 현탁제, 분산제, 유제, 또는 비경구로 투여될 수 있는 임의의 기타 투여 형태가 포함된다. 비경구 투여 형태를 제조하기 위한 기술 및 그 조성은 당업계에 공지되어 있다.In addition, the anti-tumor compounds of the present invention are preferably for parenteral administration, e.g. by intravenous, intraarterial, subcutaneous, rectal, intramuscular, orbital, intravesicular, spinal cord, intraperitoneal or intrasternal routes. It is formulated for injection via. Compositions for parenteral administration of the present invention comprise an antitumorally effective amount of a compound in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersants, emulsions, or any other dosage form that can be administered parenterally. Techniques for preparing parenteral dosage forms and compositions thereof are known in the art.
경구 또는 비경구 투여를 위한 액형 투여 형태의 제제화에 사용되는 적합한 담체에는 비수성이고 제약상 허용되는 극성 용매(예를 들면, 오일, 알콜, 아미드, 에스테르, 에테르, 케톤, 탄화수소 및 이들의 혼합물) 뿐만 아니라, 물, 식염수 용액, 덱스트로스 용액(예를 들면, DW5), 전해질 용액, 또는 수성이며 제약상 허용되는 기타 임의의 액체가 포함된다.Suitable carriers for use in formulating liquid dosage forms for oral or parenteral administration include non-aqueous and pharmaceutically acceptable polar solvents (e.g. oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof). In addition, water, saline solution, dextrose solution (eg DW5), electrolyte solution, or any other liquid that is aqueous and pharmaceutically acceptable.
비수성이며 제약상 허용되는 적합한 극성 용매에는 알콜류[예를 들면, α-글리세롤 포르말, β-글리세롤 포르말, 1,3-부틸렌글리콜, 탄소 원자수 2 내지 30의 지방족 또는 방향족 알콜(메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올, t-부탄올, 헥산올, 옥탄올, 아밀렌 수화물, 벤질 알콜, 글리세린(글리세롤), 글리콜, 헥실렌 글리콜, 테트라히드로푸르푸릴 알콜, 라우릴 알콜, 세틸 알콜 또는 스테아릴 알콜), 지방 알콜의 지방산 에스테르(폴리프로필렌 글리콜 및 폴리에틸렌 글리콜과 같은 폴리알킬렌 글리콜, 소르비탄, 수크로스 및 콜레스테롤)]; 아미드류[예를 들면, 디메틸아세트아미드(DMA), 벤질 벤조에이트 DMA, 디메틸포름아미드, N-(β-히드록시에틸)-락타미드, N,N-디메틸아세트아미드_아미드, 2-피롤리디논, 1-메틸-2-피롤리디논 또는 폴리비닐피롤리돈]; 에스테르류[예를 들면, 1-메틸-2-피롤리디논, 2-피롤리디논, 아세트산 에스테르(모노아세틴, 디아세틴 및 트리아세틴), 지방족 또는 방향족 에스테르(에틸 카프릴레이트 또는 옥타노에이트), 알킬 올레에이트, 벤질 벤조에이트, 벤질 아세테이트, 디메틸술폭시드 (DMSO), 글리세린의 에스테르(모노-, 디- 또는 트리-글리세릴 시트레이트 또는 타르트레이트), 에틸 벤조에이트, 에틸 아세테이트, 에틸 카르보네이트, 에틸 락테이트, 에틸 올레에이트, 소르비탄의 지방산 에스테르, 글리세릴 모노스테아레이트, 글리세리드 에스테르(모노-, 디- 또는 트리-글리세리드), 지방산 에스테르(이소프로필 미리스테이트), 지방산 유도된 PEG 에스테르(PEG-히드록시올레에이트 및 PEG-히드록시스테아레이트), N-메틸 피롤리디논, 플루로닉 60, 폴리옥시에틸렌 소르비톨 올레산 폴리에스테르(폴리(에톡실화)30-60소르비톨 폴리(올레에이트)2-4, 폴리(옥시에틸렌)15-20모노올레에이트, 폴리(옥시에틸렌)15-20모노 12-히드록시스테아레이트 및 폴리(옥시에틸렌)15-20모노리시놀레에이트), 폴리옥시에틸렌 소르비탄 에스테르(폴리옥시에틸렌-소르비탄 모노올레에이트, 폴리옥시에틸렌-소르비탄 모노팔미테이트, 폴리옥시에틸렌-소르비탄 모노라우레이트, 폴리옥시에틸렌-소르비탄 모노스테아레이트, 및 폴리소르베이트(Polysorbate, 등록상표) 20, 40, 60 또는 80(ICI Americas, Wilmington, DE)), 폴리비닐피롤리돈, 알킬렌옥시 개질된 지방산 에스테르(폴리옥실 40 수소화 피마자유 및 폴리옥시에틸화 피마자유, 예를 들면 크레모포르 (Cremophor, 등록상표) EL 용액 또는 크레모포르(등록상표) RH 40 용액), 당류 지방산 에스테르(즉, 단당류(리보스, 리불로스, 아라비노스, 크실로스, 릭소스 및 크실룰로스와 같은 5탄당, 글루코스, 프럭토스, 갈락토스, 만노스 및 소르보스와 같은 6탄당, 3탄당, 4탄당, 7탄당 및 8탄당), 이당류(예를 들면, 수크로스, 말토스, 락토스 및 트레할로스) 또는 올리고당류, 또는 이들의 혼합물과 C4내지 C22지방산(들)(예를 들면, 카프릴산, 카프르산, 라우르산, 미리스트산, 팔미트산 및 스테아르산과 같은 포화 지방산, 및 팔미톨레산, 올레산, 엘라이드산, 에루크산 및 리놀레산과 같은 불포화 지방산)의 축합 생성물), 또는 스테로이드계 에스테르]; 탄소 원자수 2 내지 30의 알킬, 아릴 또는 시클릭 에테르류[예를 들면, 디에틸 에테르, 테트라히드로푸란, 디메틸 이소소르비드 및 디에틸렌 글리콜 모노에틸 에테르]; 글리코푸롤[테트라히드로푸르푸릴 알콜 폴리에틸렌 글리콜 에테르]; 탄소 원자수 3 내지 30의 케톤류[예를 들면, 아세톤, 메틸 에틸 케톤 및 메틸 이소부틸 케톤]; 탄소 원자수 4 내지 30의 지방족, 지환족 또는 방향족 탄화수소류[예를 들면, 벤젠, 시클로헥산, 디클로로메탄, 디옥솔란, 헥산, n-데칸, n-도데칸, n-헥산, 술폴란, 테트라메틸렌술폰, 테트라메틸렌술폭시드, 톨루엔 또는 디메틸술폭시드(DMSO)]; 광유, 식물성 오일, 동물성 오일, 정유 또는 합성 오일[예를 들면, 지방족 또는 왁스-기재의 탄화수소, 방향족 탄화수소, 혼합된 지방족 및 방향족 기재의 탄화수소, 및 정제된 파라핀유와 같은 광유; 아마인유, 유동(油桐)유, 홍화유, 대두유, 피마자유, 면실류, 땅콩 기름, 평지씨 기름, 코코넛유, 팜유, 올리브유, 옥수수유, 옥수수 배아(胚芽) 기름, 참기름, 복숭아씨 기름 및 땅콩 기름, 및 모노-, 디- 또는 트리-글리세리드 등의 글리세리드와 같은 식물성 오일; 어류 기름, 해산물 기름, 고래 기름, 간유, 할리버(haliver), 스쿠알렌, 스쿠알란, 상어간 기름, 올레산유 및 폴리옥시에틸화 피마자유와 같은 동물성 오일]; 임의로 1개 이상의 할로겐 치환제를 갖는, 탄소 원자수 1 내지 30의 알킬 또는 아릴 할로겐화물; 염화메틸렌; 모노에탄올아민; 석유 벤진; 트롤아민; 오메가-3 폴리불포화 지방산[예를 들면, 알파-리놀렌산, 에이코사펜타엔산, 도코사펜타엔산 또는 도코사헥사엔산]; 12-히드록시스테아르산 및 폴리에틸렌 글리콜의 폴리글리콜 에스테르[솔루톨(Solutol, 등록상표) HS-15(BASF, 독일의 루드빅샤펜)]; 폴리옥시에틸렌 글리세롤; 나트륨 라우레이트; 나트륨 올레에이트; 또는 소르비탄 모노올레에이트가 포함되지만, 이에 제한되지는 않는다.Suitable non-aqueous and pharmaceutically acceptable polar solvents include alcohols such as α-glycerol formal, β-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms (methanol). , Ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycols, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol or Stearyl alcohol), fatty acid esters of fatty alcohols (polyalkylene glycols such as polypropylene glycol and polyethylene glycol, sorbitan, sucrose and cholesterol); Amides [eg, dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N- (β-hydroxyethyl) -lactamide, N, N-dimethylacetamide_amide, 2-pyrroli Dinon, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidone]; Esters [eg 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetic acid esters (monoacetin, diacetin and triacetin), aliphatic or aromatic esters (ethyl caprylate or octanoate) ), Alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), esters of glycerin (mono-, di- or tri-glyceryl citrate or tartrate), ethyl benzoate, ethyl acetate, ethyl carbox Carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, glyceryl monostearate, glyceride esters (mono-, di- or tri-glycerides), fatty acid esters (isopropyl myristate), fatty acid derived PEG Esters (PEG-hydroxyoleate and PEG-hydroxystearate), N-methyl pyrrolidinone, Pluronic 60, polyoxyethylene sorbitol oleic acid Lee ester (poly (ethoxylated) 30-60 sorbitol poly (oleate) 2-4, poly (oxyethylene) 15-20 monooleate, poly (oxyethylene) 15-20 mono 12-hydroxy stearate, and poly (Oxyethylene) 15-20 monoricinoleate), polyoxyethylene sorbitan ester (polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, Polyoxyethylene-sorbitan monostearate, and polysorbate® 20, 40, 60 or 80 (ICI Americas, Wilmington, DE)), polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters (Polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oil, such as Cremophor® EL solution or Cremophor® RH 40 solution), sugar fatty acid esters (i.e. monosaccharides ( Ribose, Rebull Pentose, such as glucose, fructose, galactose, mannose, and sorbose, hexasaccharides, trisaccharides, saccharides, saccharides and octanes, such as sugar, arabinose, xylose, lyxose and xylulose, disaccharides ( For example sucrose, maltose, lactose and trehalose) or oligosaccharides, or mixtures thereof and C 4 to C 22 fatty acid (s) (e.g. caprylic acid, capric acid, lauric acid, micro Condensation products of saturated fatty acids such as listic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, oleic acid, erucic acid and linoleic acid), or steroid esters; Alkyl, aryl or cyclic ethers having 2 to 30 carbon atoms [eg, diethyl ether, tetrahydrofuran, dimethyl isosorbide and diethylene glycol monoethyl ether]; Glycofurol [tetrahydrofurfuryl alcohol polyethylene glycol ether]; Ketones having 3 to 30 carbon atoms [eg, acetone, methyl ethyl ketone and methyl isobutyl ketone]; Aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms [eg, benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetra Methylene sulfone, tetramethylene sulfoxide, toluene or dimethyl sulfoxide (DMSO)]; Mineral oils, such as mineral oils, vegetable oils, animal oils, essential oils or synthetic oils [eg, aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oils; Linseed oil, floating oil, safflower oil, soybean oil, castor oil, cottonseeds, peanut oil, rapeseed oil, coconut oil, palm oil, olive oil, corn oil, corn germ oil, sesame oil, peach seed oil and Vegetable oils such as peanut oil and glycerides such as mono-, di- or tri-glycerides; Animal oils such as fish oil, seafood oil, whale oil, cod liver oil, haliber, squalene, squalane, shark liver oil, oleic oil and polyoxyethylated castor oil; Alkyl or aryl halides having 1 to 30 carbon atoms, optionally having one or more halogen substituents; Methylene chloride; Monoethanolamine; Petroleum benzine; Trolamine; Omega-3 polyunsaturated fatty acids [eg, alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid]; Polyglycol esters of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15 (BASF, Ludwigshafen, Germany)); Polyoxyethylene glycerol; Sodium laurate; Sodium oleate; Or sorbitan monooleate, but is not limited thereto.
본 발명에 사용하기 위한 제약상 허용되는 기타 용매는 당업자에게 잘 공지되어 있으며, 문헌[The Chemotherapy Source Book(Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients(American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics(G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics(Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms(H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences(A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, PA, 1995), TheUnited States Pharmacopeia 24, The National Formulary 19(National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et al., 및 Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927(1963)]에서 확인할 수 있다.Pharmaceutically acceptable other solvents for use in the present invention are well known to those skilled in the art and include The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical). Society of Great Britain, London, England, 1968), Modern Pharmaceutics (G. Banker et al., Eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms (H. Lieberman et al., Eds.,) (Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed ., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19 (National Publishing, Philadelphia, PA, 2000), AJ Spiegel et al., And Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, no. 10, pp. 917-927 (1963).
바람직한 용매에는 트리글리세리드가 풍부한 오일, 예를 들면 홍화유, 대두유 또는 이들의 혼합물, 및 폴리옥실 40 수소화 피마자유 및 폴리옥시에틸화 피마자유(예를 들면, 크레모포르(등록상표) EL 용액 또는 크레모포르(등록상표) RH 40 용액) 등의 알킬렌옥시 개질된 지방산 에스테르와 같이 항종양 화합물을 안정화시키는 것으로 공지된 용매가 포함된다. 상업적으로 시판되는 트리글레세리드에는 인트라리피드(Intralipid, 등록상표) 유화된 대두유(Kabi-Pharmacia Inc., 스웨덴의 스톡홀름), 뉴트라리피드(Nutralipid, 등록상표) 유제(McGaw, Irvine, California), 리포신(Lyposyn, 등록상표) Ⅱ 20% 유제(용액 1 ㎖ 당 홍화유 100 ㎎, 대두유 100 ㎎, 계란 인지질 12 ㎎ 및 글리세린 25 ㎎을 함유하는 20% 지방 유제 용액; Abbott Laboratories, 미국 일리노이주의 시카고), 리포신(등록상표) Ⅲ 2% 유제(용액 1 ㎖ 당 홍화유 100 ㎎, 대두유 100 ㎎, 계란 인지질 12 ㎎ 및 글리세린 25 ㎎을 함유하는 2% 지방 유제 용액; Abbott Laboratories, 미국 일리노이주의 시카고), 총 지방산 함량을 기준으로 25 중량% 내지 100 중량%의 도코사헥사에노일기를 함유하는 천연 또는 합성 글리세롤 유도체(다스코(Dhasco, 등록상표; Martek Biosciences Corp., 미국 메릴랜드주의 콜럼비아), DHA 마구로(DHA Maguro, 등록상표; Daito Enterprises, 미국 캘리포니아주의 로스앤젤레스), 소이아칼(Soyacal, 등록상표) 및 트래브에멀전(Travemulsion, 등록상표))가 포함된다. 항종양 화합물을 용해시켜 용액 및 유제 등을 형성하는데 바람직한 용매는 에탄올이다.Preferred solvents include triglyceride-rich oils such as safflower oil, soybean oil or mixtures thereof, and polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oil (e.g., Cremophor® EL solution or Cremo Solvents known to stabilize anti-tumor compounds, such as alkyleneoxy modified fatty acid esters such as Fort® RH 40 solution). Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid® emulsions (McGaw, Irvine, California), Lipo Lyposyn® II 20% emulsion (20% fat emulsion containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phospholipid and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), Liposin® III 2% emulsion (2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phospholipid and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois, USA), total Natural or synthetic glycerol derivatives containing from 25% to 100% by weight of docosahexaenoyl groups, based on fatty acid content (Dhasco, Martek Biosciences Corp., Maryland, USA It includes Daito Enterprises, Los Angeles, California, USA, Attention), Soy ahkal (Soyacal, registered trademark) and trafficking probe emulsion (Travemulsion, registered trademark)); Rum Via) harnesses with DHA (DHA Maguro, a registered trademark. Preferred solvent for dissolving the anti-tumor compound to form solutions, emulsions and the like is ethanol.
제약 산업 분야에 잘 공지된 다양한 목적을 위해, 부가의 미량 성분이 본 발명의 조성물에 포함될 수 있다. 이들 성분은 대부분, 항종양 화합물의 투여된 부위에의 보유성을 향상시키는 특성, 조성물의 안정성을 보호하는 특성, pH를 조절하는 특성 및 항종양 화합물의 제약 제제로의 가공을 촉진하는 특성 등을 부여할 것이다. 이들 성분 각각은 바람직하게는 총 조성물의 약 15 중량% 미만으로 존재하고, 더욱 바람직하게는 총 조성물의 약 5 중량% 미만으로 존재하며, 가장 바람직하게는 총 조성물의 약 0.5 중량% 미만으로 존재한다. 충전제 또는 희석제와 같은 일부 성분들은, 제약 제제화 분야에 잘 공지된 바와 같이 총 조성물의 90 중량% 이하로 존재할 수 있다. 이러한 첨가제에는 탁산의 재침전을 방지하기 위한 동결방지제, 계면활성제, 습윤제 또는 유화제(예를 들면, 레시틴, 폴리소르베이트-80, 트윈(Tween, 등록상표) 80, 플루로닉 60, 폴리옥시에틸렌 스테아레이트), 방부제(예를 들면, 에틸-p-히드록시벤조에이트), 미생물 방부제(예를 들면, 벤질 알콜, 페놀, m-크레졸, 클로로부탄올, 소르브산, 티메로살 및 파라벤), pH 조정을 위한 보조제 또는 완충제(예를 들면, 산, 염기, 아세트산나트륨, 소르비탄 모노라우레이트), 삽투압 조정을 위한 보조제(예를 들면, 글리세린), 증점제(예를 들면, 모노스테아르산 알루미늄, 스테아르산, 세틸 알콜, 스테아릴 알콜, 구아검(guar gum), 메틸 셀룰로스, 히드록시프로필셀룰로스, 트리스테아린, 세틸 왁스 에스테르, 폴리에틸렌 글리콜), 착색제, 염료, 유동 보조제, 비휘발성 실리콘(예를 들면, 시클로메티콘), 점토(예를 들면, 벤토나이트), 접착제, 벌크화제, 착향료, 감미제, 흡수제, 충전제(예를 들면, 락토스, 수크로스, 만니톨 또는 소르비톨과 같은 당, 셀룰로스 또는 인산칼슘), 희석제(예를 들면, 물, 식염수 및 전해질 용액), 결합제(예를 들면, 옥수수 전분, 밀 전분, 쌀 전분 또는 감자 전분과 같은 전분, 젤라틴, 트라가칸트 검, 메틸 셀룰로스, 히드록시프로필 메틸셀룰로스, 나트륨 카르복시메틸 셀룰로스, 폴리비닐피롤리돈, 당, 중합체 및 아카시아), 붕해제(예를 들면, 옥수수 전분, 밀 전분, 쌀 전분, 감자 전분 또는 카르복시메틸 전분과 같은 전분, 가교결합된 폴리비닐 피롤리돈, 한천, 알긴산 또는 알긴산나트륨과 같은 그의 염, 크로스카르멜로스 나트륨 또는 크로스포비돈), 윤활제 (예를 들면, 실리카, 활석, 스테아르산 또는 스테아르산마그네슘과 같은 그의 염, 또는 폴리에틸렌 글리콜), 코팅제(예를 들면, 아라비아 검을 비롯한 농축된 당 용액, 활석, 폴리비닐 피롤리돈, 카르보폴 겔, 폴리에틸렌 글리콜 또는 이산화티타늄) 및 산화방지제(예를 들면, 메타중아황산나트륨, 중아황산나트륨, 아황산나트륨, 덱스트로스, 페놀 및 티오페놀)가 포함된다.For various purposes well known in the pharmaceutical industry, additional trace ingredients can be included in the compositions of the present invention. Most of these components are characterized by improving the retention of the anti-tumor compound at the administered site, protecting the stability of the composition, adjusting the pH, promoting the processing of the anti-tumor compound into pharmaceutical formulations, and the like. Will give. Each of these components is preferably present at less than about 15% by weight of the total composition, more preferably at less than about 5% by weight of the total composition, and most preferably at less than about 0.5% by weight of the total composition. . Some components, such as fillers or diluents, may be present up to 90% by weight of the total composition, as is well known in the pharmaceutical formulation art. These additives include cryoprotectants, surfactants, wetting agents or emulsifiers (eg lecithin, polysorbate-80, Tween® 80, Pluronic 60, polyoxyethylene to prevent reprecipitation of taxanes). Stearates), preservatives (eg ethyl-p-hydroxybenzoate), microbial preservatives (eg benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and parabens), pH Adjuvants or buffers (eg, acid, base, sodium acetate, sorbitan monolaurate) for the adjustment, adjuvants (eg, glycerin) for the adjustment of the osmotic pressure, thickeners (eg, aluminum monostearate, Stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax ester, polyethylene glycol), colorant, dye, flow aid, nonvolatile silicone (E.g. cyclomethicone), clays (e.g. bentonite), adhesives, bulking agents, flavoring agents, sweeteners, absorbents, fillers (e.g. sugars such as lactose, sucrose, mannitol or sorbitol, cellulose or Calcium phosphate), diluents (e.g. water, saline and electrolyte solutions), binders (e.g. starches such as corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth gum, methyl cellulose, hydride) Oxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers and acacia), disintegrants (e.g., starch such as corn starch, wheat starch, rice starch, potato starch or carboxymethyl starch, crosslinking) Bound polyvinyl pyrrolidone, agar, salts such as alginic acid or sodium alginate, croscarmellose sodium or crospovidone), lubricants (for example silica, talc, stearic acid or Salts such as magnesium stearate, or polyethylene glycol), coatings (e.g., concentrated sugar solutions, including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol or titanium dioxide) and antioxidants (e.g. For example, sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenol and thiophenol).
바람직한 실시양태에서, 본 발명의 제약 조성물은 제약상 허용되는 1종 이상의 비수성 용매, 및 에탄올 중의 용해도가 약 100, 200, 300, 400, 500, 600, 700 또는 800 ㎎/㎖ 이상인 항종양 화합물을 포함한다. 특정 이론에 얽매이려는 것은 아니지만, 항종양 화합물의 에탄올 중의 용해도는 그의 효능과 직접적으로 관련된 것으로 생각된다. 또한, 항종양 화합물은 용액으로부터 결정화될 수 있다. 즉,화합물 1393과 같은 결정질 항종양 화합물은 용매 중에 용해되어 용액을 형성한 후, 용매의 증발시 어떠한 무정형 항종양 화합물도 생성하지 않으면서 재결정화될 수 있다. 또한, 항종양 화합물의 ID50 값(즉, 콜로니 형성을 50% 억제하는 약물 농도)은, 본 명세서의 실시예에 기재된 과정에 따라 측정시 파클리탁셀(paclitaxel)에 비해 4, 5, 6, 7, 8, 9 또는 10 배 이상 더 낮은 것이 바람직하다.In a preferred embodiment, the pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable non-aqueous solvent and an anti-tumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg / ml. It includes. Without wishing to be bound by any theory, it is believed that the solubility of the antitumor compound in ethanol is directly related to its efficacy. In addition, antitumor compounds can be crystallized from solution. That is, crystalline anti-tumor compounds such as compound 1393 may be dissolved in a solvent to form a solution and then recrystallized without producing any amorphous anti-tumor compound upon evaporation of the solvent. In addition, the ID50 value of the anti-tumor compound (ie drug concentration that inhibits colony formation by 50%) is 4, 5, 6, 7, 8 compared to paclitaxel as measured according to the procedures described in the Examples herein. It is preferred to be at least 9 or 10 times lower.
이러한 경로에 의한 투여 형태는, 예를 들어 환자의 생리적 조건, 투여가 치료 목적인지 예방 목적인지의 여부, 그리고 전문가에게 공지되고 전문가가 평가할 수 있는 기타 인자에 따라 연속적 또는 단속적일 수 있다.Dosage forms by this route may be continuous or intermittent, for example, depending on the physiological condition of the patient, whether the administration is for therapeutic or prophylactic purposes, and other factors known to the expert and evaluable by the expert.
본 발명 제약 조성물의 투여량 및 투여 계획은 암을 치료하는 당업자에 의해 쉽게 결정될 수 있다. 항종양 화합물의 투여량은 환자의 연령, 성별, 건강 상태 및 체중, (존재한다면) 수반되는 치료의 종류, 치료 빈도 및 원하는 효과의 본질에 따라 달라질 것으로 이해된다. 어떠한 투여 방식에 대해서도, 전달되는 실제 항종양 화합물의 양 뿐만 아니라 본 명세서에서 원하는 유익한 효과를 성취하기 위해 필요한 투여 일정은, 부분적으로는 항종양 화합물의 생체이용율, 치료될 질환, 바람직한 투여량 및 당업자에게 명백한 기타 인자들과 같은 인자에 따라 달라질 것이다. 본 발명에 있어서, 동물(특히, 인간)에게 투여되는 투여량은 적당한 기간에 걸쳐 동물에서 원하는 치료적 반응이 나타날 수 있을 정도로 충분해야 한다. 바람직하게는, 경구 투여되든지 다른 경로로 투여되든지 무관하게, 항종양 화합물의 유효량은 그 경로로 투여되었을 때 원하는 치료적 반응을 초래할 수 있는 임의의 양이다. 경구 투여용 화합물은 바람직하게는, 1종 이상의 경구용 제제의 단일 투여량이 환자의 체표면적 1 ㎡ 당 20 ㎎ 이상의 항종양 화합물을 함유하거나, 또는 환자의 체표면적 1 ㎡ 당 50, 100, 150, 200, 300, 400 또는 500 ㎎ 이상의 항종양 화합물을 함유하도록 하는(사람 평균 체표면적은 1.8 ㎡임) 방식으로 제조된다. 바람직하게는, 경구 투여용 조성물의 단일 투여량이 환자의 체표면적 1 ㎡ 당 약 20 내지 약 600 ㎎의 항종양 화합물을 함유하며, 더욱 바람직하게는 약 25 내지 약 400 ㎎/㎡, 더더욱 바람직하게는 약 40 내지 약 300 ㎎/㎡, 가장 바람직하게는 약 50 내지 약 200 ㎎/㎡의 항종양 화합물을 함유한다. 비경구 투여용 조성물은 바람직하게는, 단일 투여량이 환자의 체표면적 1 ㎡ 당 20 ㎎ 이상의 항종양 화합물을 함유하거나, 또는 환자의 체표면적 1 ㎡ 당 40, 50, 100, 150, 200, 300, 400 또는 500 ㎎ 이상의 항종양 화합물을 함유하도록 하는 방식으로 제조된다. 바람직하게는, 1종 이상의 비경구용 제제의 단일 투여량이 환자의 체표면적 1 ㎡ 당 약 20 내지 약 500 ㎎의 항종양 화합물을 함유하며, 더욱 바람직하게는 약 40 내지 약 400 ㎎/㎡, 더더욱 바람직하게는 약 60 내지 약 350 ㎎/㎡의 항종양 화합물을 함유한다. 그러나, 투여량은 원하는 치료 효과를 얻기 위해 필요에 따라 조정될 수 있는 투여 일정에 따라 달라질 수 있다. 본 명세서에 제공된 효과적인 투여량의 범위는 본 발명을 제한할 의도로 기재된 것이 아니며, 바람직한 투여량의 범위를 나타내기 위한 것임을 알아야 한다. 가장 바람직한 투여량은 불필요한 실험없이 당업자에 의해 이해되고 결정될 수 있는 바와 같이, 개개의 환자에 맞게 달라질 것이다.Dosages and dosing regimens of the pharmaceutical compositions of the invention can be readily determined by one skilled in the art of treating cancer. It is understood that the dosage of the antitumor compound will vary depending on the age, sex, health condition and weight of the patient, the type of treatment (if any) involved, the frequency of treatment and the nature of the desired effect. For any mode of administration, the amount of actual antitumor compound delivered, as well as the schedule of administration necessary to achieve the desired beneficial effect herein, depends in part on the bioavailability of the antitumor compound, the disease to be treated, the desired dosage, and the skilled person. It will depend on factors such as other factors that are obvious to you. In the present invention, the dosage administered to an animal (especially a human) should be sufficient to allow for the desired therapeutic response in the animal over a suitable period of time. Preferably, whether administered orally or by other route, an effective amount of an anti-tumor compound is any amount that can result in the desired therapeutic response when administered by that route. The compound for oral administration preferably comprises a single dose of one or more oral preparations containing at least 20 mg of anti-tumor compound per m 2 of the patient's body surface area, or 50, 100, 150, per m 2 of the body surface area of the patient. It is prepared in such a way that it contains at least 200, 300, 400 or 500 mg of anti-tumor compound (human average body surface area is 1.8 m 2). Preferably, a single dose of the composition for oral administration contains about 20 to about 600 mg antitumor compound per 1 m 2 of body surface area of the patient, more preferably about 25 to about 400 mg / m 2, even more preferably It contains about 40 to about 300 mg / m 2, most preferably about 50 to about 200 mg / m 2 of antitumor compound. Compositions for parenteral administration preferably contain a single dose containing at least 20 mg of antitumor compound per m 2 of the patient's body surface area, or 40, 50, 100, 150, 200, 300, per m 2 of the patient's body surface area. It is prepared in such a way that it contains at least 400 or 500 mg of antitumor compound. Preferably, the single dosage of the one or more parenteral preparations contains about 20 to about 500 mg of antitumor compound per m 2 of body surface area of the patient, more preferably about 40 to about 400 mg / m 2, even more preferred Preferably from about 60 to about 350 mg / m 2. However, the dosage can vary depending on the dosing schedule, which can be adjusted as needed to achieve the desired therapeutic effect. It is to be understood that the range of effective dosages provided herein is not intended to limit the present invention and is intended to represent the range of preferred dosages. The most preferred dosage will vary for each patient, as can be understood and determined by one skilled in the art without unnecessary experimentation.
액형 제약 조성물 중의 항종양 화합물의 농도는 바람직하게는 조성물 1 ㎖당 약 0.01 ㎎ 내지 약 10 ㎎이며, 더욱 바람직하게는 약 0.1 ㎎/㎖ 내지 약 7 ㎎/㎖, 더더욱 바람직하게는 약 0.5 ㎎/㎖ 내지 약 5 ㎎/㎖, 가장 바람직하게는 약 1.5 ㎎/㎖ 내지 약 4 ㎎/㎖이다. 항종양 화합물은 용액 중에서 낮은 농도인 경우에 용해도가 크기 때문에, 일반적으로 비교적 낮은 농도가 바람직하다. 경구 투여용 고형 제약 조성물 중의 항종양 화합물의 농도는 조성물의 총 중량을 기준으로 약 5 중량% 내지 약 50 중량%가 바람직하며, 더욱 바람직하게는 약 8 중량% 내지 약 40 중량%, 가장 바람직하게는 약 10 중량% 내지 약 30 중량% 사이이다.The concentration of the anti-tumor compound in the liquid pharmaceutical composition is preferably from about 0.01 mg to about 10 mg per ml of the composition, more preferably from about 0.1 mg / ml to about 7 mg / ml, even more preferably about 0.5 mg / Ml to about 5 mg / ml, most preferably about 1.5 mg / ml to about 4 mg / ml. Since anti-tumor compounds have high solubility at low concentrations in solution, relatively low concentrations are generally preferred. The concentration of the anti-tumor compound in the solid pharmaceutical composition for oral administration is preferably about 5 wt% to about 50 wt%, more preferably about 8 wt% to about 40 wt%, most preferably based on the total weight of the composition Is between about 10% and about 30% by weight.
한 실시양태에서, 경구 투여용 용액제는 항종양 화합물을 용해시킬 수 있는 임의의 제약상 허용되는 용매(예를 들면, 에탄올 또는 염화메틸렌)에 상기 화합물을 용해시켜 용액을 형성함으로써 제조된다. 크레모포르(등록상표) EL 용액과 같이 용액 상태인 적합한 부피의 담체를 교반하에 상기 용액에 가하여, 환자에게 경구 투여할 수 있는 제약상 허용되는 용액제를 생성한다. 필요한 경우, 이러한 용액제는 경구용 제제 중에 특정 농도로 투여할 때 생리적 부작용을 유발하는 것으로 당업계에 공지된 에탄올을 최소량으로 함유하거나 함유하지 않도록 제제화될 수 있다.In one embodiment, solutions for oral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. A suitable volume of carrier in solution, such as Cremophor® EL solution, is added to the solution under agitation to produce a pharmaceutically acceptable solution that can be administered orally to the patient. If desired, such solutions may be formulated with or without a minimum amount of ethanol known in the art to cause physiological side effects when administered at a particular concentration in an oral formulation.
또다른 실시양태에서, 경구 투여용 분말 또는 정제는 항종양 화합물을 용해시킬 수 있는 임의의 제약상 허용되는 용매(예를 들면, 에탄올 또는 염화메틸렌)에 상기 화합물을 용해시켜 용액을 형성함으로써 제조된다. 이 용매는 용액이 진공하에서 건조될 때, 임의로 증발될 수 있다. 건조시키기 전에, 크레모포르(등록상표) EL 용액과 같은 부가의 담체를 용액에 가할 수 있다. 생성된 용액을 진공하에서건조하여 유리를 형성한다. 이 유리를 결합제와 혼합하여 분말을 형성한다. 이 분말은 충전제 또는 종래의 다른 정제 보조제와 혼합된 후 가공되어, 환자에게 경구 투여할 수 있는 정제를 형성할 수 있다. 또한, 상기 분말을 상기 기재된 바와 같은 액형 담체에 가하여 경구 투여용 용액제, 유제 또는 현탁제 등을 형성할 수 있다.In another embodiment, powders or tablets for oral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. . This solvent can optionally be evaporated when the solution is dried under vacuum. Prior to drying, additional carriers such as Cremophor® EL solution can be added to the solution. The resulting solution is dried under vacuum to form a glass. This glass is mixed with a binder to form a powder. This powder may be mixed with fillers or other conventional tablet aids and then processed to form tablets for oral administration to a patient. The powder may also be added to a liquid carrier as described above to form solutions, emulsions or suspensions for oral administration.
비경구 투여용 유제는 항종양 화합물을 용해시킬 수 있는 임의의 제약상 허용되는 용매(예를 들면, 에탄올 또는 염화메틸렌)에 상기 화합물을 용해시켜 용액을 형성함으로써 제조된다. 리포신(등록상표) Ⅱ 또는 리포신(등록상표) Ⅲ 유제와 같이 유제 상태인 적합한 부피의 담체를 교반하에 상기 용액에 가하여, 환자에게 비경구 투여할 수 있는 제약상 허용되는 유제를 생성한다. 필요한 경우, 이러한 유제는 비경구용 제제 중에 특정 농도로 투여할 때 생리적 부작용을 유발하는 것으로 당업계에 공지된 에탄올 또는 크레모포르(등록상표) 용액을 최소량으로 함유하거나 함유하지 않도록 제제화될 수 있다.Emulsions for parenteral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent capable of dissolving the anti-tumor compound (eg, ethanol or methylene chloride) to form a solution. A suitable volume of carrier in tangent, such as liposin® II or liposin® III emulsion, is added to the solution under stirring to produce a pharmaceutically acceptable emulsion that can be parenterally administered to a patient. If desired, such emulsions may be formulated with or without minimal amounts of ethanol or Cremophor® solutions known in the art to cause physiological side effects when administered at certain concentrations in parenteral formulations.
비경구 투여용 용액제는 항종양 화합물을 용해시킬 수 있는 임의의 제약상 허용되는 용매(예를 들면, 에탄올 또는 염화메틸렌)에 상기 화합물을 용해시켜 용액을 형성함으로써 제조된다. 크레모포르(등록상표) 용액과 같이 용액 상태인 적합한 부피의 담체를 교반하에 상기 용액에 가하여, 환자에게 비경구 투여할 수 있는 제약상 허용되는 용액제를 생성한다. 필요한 경우, 이러한 용액제는 비경구용 제제 중에 특정 농도로 투여할 때 생리적 부작용을 유발하는 것으로 당업계에 공지된 에탄올 또는 크레모포르(등록상표) 용액을 최소량으로 함유하거나 함유하지 않도록 제제화될 수 있다.Solutions for parenteral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. A suitable volume of carrier in solution, such as a Cremophor® solution, is added to the solution under agitation to produce a pharmaceutically acceptable solution for parenteral administration to the patient. If desired, such solutions may be formulated with or without minimal amounts of ethanol or Cremophor® solutions known in the art to cause physiological side effects when administered at specific concentrations in parenteral formulations. .
필요한 경우, 경구 또는 비경구 투여를 위해 상기 기재된 유제 또는 용액제는, 식염수와 같은 제약상 허용되는 임의의 액체로 희석된 형태 또는 농축된 형태로 Ⅳ 백, 바이알 또는 종래의 다른 용기에 패키징되어, 당업계에 공지된 바와 같은 사용전 상태의 허용가능한 탁산 농축물을 형성할 수 있다.If desired, the emulsions or solutions described above for oral or parenteral administration may be packaged in IV bags, vials or other conventional containers in diluted or concentrated form with any pharmaceutically acceptable liquid, such as saline, Allowable taxane concentrates can be formed in their pre-use state as known in the art.
<정의><Definition>
본 명세서에 사용된 "탄화수소" 및 "히드로카르빌"이란 용어는 오직 탄소 및 수소 원소로만 이루어진 유기 화합물 또는 라디칼을 의미한다. 이러한 잔기에는 알킬, 알케닐, 알키닐 및 아릴 잔기가 포함된다. 또한, 이들 잔기에는 알크아릴, 알켄아릴 및 알킨아릴과 같은, 다른 지방족 또는 시클릭 탄화수소기로 치환된 알킬, 알케닐, 알키닐 및 아릴 잔기가 포함된다. 달리 언급하지 않은 한, 이들 잔기는 바람직하게는 1 내지 20개의 탄소 원자를 포함한다.As used herein, the terms "hydrocarbon" and "hydrocarbyl" refer to organic compounds or radicals consisting solely of carbon and hydrogen elements. Such residues include alkyl, alkenyl, alkynyl and aryl residues. These residues also include alkyl, alkenyl, alkynyl and aryl residues substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless stated otherwise, these moieties preferably comprise 1 to 20 carbon atoms.
본 명세서에 기재된 "치환된 히드로카르빌" 잔기란 탄소 사슬 원자가 질소, 산소, 규소, 인, 붕소, 황 또는 할로겐 원자와 같은 헤테로원자로 치환된 잔기를 비롯한, 1개 이상의 탄소가 아닌 원자로 치환된 히드로카르빌 잔기를 의미한다. 이들 치환체에는 할로겐, 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 케토, 아실, 아실옥시, 니트로, 아미노, 아미도, 니트로, 시아노, 티올, 케탈, 아세탈, 에스테르 및 에테르가 포함된다.As used herein, a "substituted hydrocarbyl" moiety is a hydro substituted with one or more non-carbon atoms, including residues where the carbon chain atoms are substituted with heteroatoms such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms. Means a carbyl residue. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketal, Acetals, esters and ethers are included.
"헤테로원자"란 용어는 탄소 및 수소 이외의 원자를 의미한다.The term "heteroatom" refers to atoms other than carbon and hydrogen.
본 명세서에 기재된 "헤테로치환된 메틸" 잔기란 탄소 원자가 1개 이상의 헤테로원자(예를 들면, 질소, 산소, 규소, 인, 붕소, 황 또는 할로겐 원자임) 및 임의로는 수소와 공유결합되어 있는 메틸기를 의미한다. 다시 말해서, 헤테로원자는 다른 원자로 치환되어 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 옥시, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 또는 에테르 잔기를 형성할 수 있다.A "heterosubstituted methyl" residue described herein refers to a methyl group having a carbon atom covalently bonded to one or more heteroatoms (eg, nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms) and optionally hydrogen Means. In other words, heteroatoms are substituted with other atoms such as heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, It can form ester or ether moieties.
본 명세서에 기재된 "헤테로치환된 아세테이트" 잔기란 메틸기의 탄소 원자가 1개 이상의 헤테로원자(예를 들면, 질소, 산소, 규소, 인, 붕소, 황 또는 할로겐 원자임) 및 임의로는 수소와 공유결합되어 있는 아세테이트기를 의미한다. 다시 말해서, 헤테로원자는 다른 원자로 치환되어 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 옥시, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 또는 에테르 잔기를 형성할 수 있다.A "heterosubstituted acetate" residue described herein means that the carbon atom of the methyl group is covalently bonded with one or more heteroatoms (eg, nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms) and optionally hydrogen Acetate group present. In other words, heteroatoms are substituted with other atoms such as heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, It can form ester or ether moieties.
달리 언급하지 않는 한, 본 명세서에 기재된 알킬기는 바람직하게는 1 내지 8개의 탄소 원자를 주쇄에 함유하고 20개 이하의 탄소 원자를 함유하는 저급 알킬이다. 알킬기는 직쇄, 분지쇄 또는 시클릭일 수 있으며, 여기에는 메틸, 에틸, 프로필, 이소프로필, 부틸 및 헥실 등이 포함된다.Unless stated otherwise, the alkyl groups described herein are preferably lower alkyls containing from 1 to 8 carbon atoms in the main chain and containing up to 20 carbon atoms. Alkyl groups may be straight, branched or cyclic, including methyl, ethyl, propyl, isopropyl, butyl and hexyl and the like.
달리 언급하지 않는 한, 본 명세서에 기재된 알케닐기는 바람직하게는 2 내지 8개의 탄소 원자를 주쇄에 함유하고 20개 이하의 탄소 원자를 함유하는 저급 알케닐이다. 알케닐기는 직쇄, 분지쇄 또는 시클릭일 수 있으며, 여기에는 에테닐, 프로페닐, 이소프로페닐, 부테닐, 이소부테닐 및 헥세닐 등이 포함된다.Unless stated otherwise, the alkenyl groups described herein are preferably lower alkenyl containing from 2 to 8 carbon atoms in the main chain and containing up to 20 carbon atoms. Alkenyl groups may be straight, branched or cyclic, including ethenyl, propenyl, isopropenyl, butenyl, isobutenyl and hexenyl and the like.
달리 언급하지 않는 한, 본 명세서에 기재된 알키닐기는 바람직하게는 2 내지 8개의 탄소 원자를 주쇄에 함유하고 20개 이하의 탄소 원자를 함유하는 저급 알키닐이다. 알키닐기는 직쇄 또는 분지쇄일 수 있으며, 여기에는 에티닐, 프로피닐, 부티닐, 이소부티닐 및 헥세닐 등이 포함된다.Unless stated otherwise, the alkynyl groups described herein are preferably lower alkynyls containing from 2 to 8 carbon atoms in the main chain and containing up to 20 carbon atoms. Alkynyl groups can be straight or branched, including ethynyl, propynyl, butynyl, isobutynyl, hexenyl and the like.
본 명세서에 단독으로 또는 다른 기의 일부분으로서 사용되는 "아릴" 또는 "아르"란 용어는 임의로 치환된 호모시클릭 방향족 기, 바람직하게는 고리 부분에 6 내지 12개의 탄소를 함유하는 모노시클릭 또는 비시클릭 기(예를 들면, 페닐, 비페닐, 나프틸, 치환된 페닐, 치환된 비페닐 또는 치환된 나프틸)를 의미한다. 페닐 및 치환된 페닐이 더욱 바람직한 아릴이다.As used herein, alone or as part of another group, the term “aryl” or “ar” refers to an optionally substituted homocyclic aromatic group, preferably monocyclic containing 6 to 12 carbons in the ring portion, or Bicyclic group (eg, phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl). Phenyl and substituted phenyl are more preferred aryls.
본 명세서에 단독으로 또는 다른 기의 일부분으로서 사용되는 "할로겐" 또는 "할로"란 용어는 염소, 브롬, 불소 및 요오드를 나타낸다.The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine.
본 명세서에 단독으로 또는 다른 기의 일부분으로서 사용되는 "헤테로시클로" 또는 "헤테로시클릭"이란 용어는 1개 이상의 고리에 1개 이상의 헤테로원자, 바람직하게는 각각의 고리에 5개 또는 6개의 헤테로원자를 갖는, 임의로 치환될 수 있고 완전히 포화되거나 불포화된 상태의 모노시클릭 또는 비시클릭 형태의 방향족 또는 비방향족 기를 의미한다. 바람직하게는 헤테로시클로기가 고리에 1개 또는 2개의 산소 원자, 1개 또는 2개의 황 원자 및(또는) 1개 내지 4개의 질소 원자를 가지며, 탄소 또는 헤테로원자를 통해 분자의 나머지 부분과 결합될 수 있다. 헤테로시클로의 예에는 푸릴, 티에닐, 피리딜, 옥사졸릴, 피롤릴, 인돌릴, 퀴놀리닐 및 이소퀴놀리닐 등과 같은 헤테로방향족 기가 포함된다. 치환체의 예에는 히드로카르빌, 치환된 히드로카르빌, 케토, 히드록시, 보호된 히드록시, 아실, 아실옥시,알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 할로겐, 아미도, 아미노, 니트로, 시아노, 티올, 케탈, 아세탈, 에스테르 및 에테르로 구성된 군으로부터 선택되는 1개 이상의 치환체가 포함된다.The term "heterocyclo" or "heterocyclic" as used herein alone or as part of another group refers to one or more heteroatoms in one or more rings, preferably five or six heteros in each ring. It means an aromatic or non-aromatic group in the monocyclic or bicyclic form, optionally substituted and fully saturated or unsaturated having an atom. Preferably the heterocyclo group has one or two oxygen atoms, one or two sulfur atoms and / or one to four nitrogen atoms in the ring and is bonded to the rest of the molecule via carbon or heteroatoms. Can be. Examples of heterocyclo include heteroaromatic groups such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl and isoquinolinyl and the like. Examples of substituents include hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cya One or more substituents selected from the group consisting of furnaces, thiols, ketals, acetals, esters and ethers.
본 명세서에 단독으로 또는 다른 기의 일부분으로서 사용되는 "헤테로방향족 기"란 용어는 1개의 고리에 1개 이상의 헤테로원자, 바람직하게는 각각의 고리에 5개 또는 6개의 헤테로원자를 갖는, 임의로 치환될 수 있는 방향족 기를 의미한다. 바람직하게는 헤테로방향족 기가 고리에 1개 또는 2개의 산소 원자, 1개 또는 2개의 황 원자 및(또는) 1개 내지 4개의 질소 원자를 가지며, 탄소 또는 헤테로원자를 통해 분자의 나머지 부분과 결합될 수 있다. 헤테로방향족 기의 예에는 푸릴, 티에닐, 피리딜, 옥사졸릴, 피롤릴, 인돌릴, 퀴놀리닐 또는 이소퀴놀리닐 등이 포함된다. 치환체의 예에는 히드로카르빌, 치환된 히드로카르빌, 케토, 히드록시, 보호된 히드록시, 아실, 아실옥시, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 할로겐, 아미도, 아미노, 니트로, 시아노, 티올, 케탈, 아세탈, 에스테르 및 에테르로 구성된 군으로부터 선택되는 1개 이상의 치환체가 포함된다.As used herein, alone or as part of another group, the term “heteroaromatic group” is optionally substituted with one or more heteroatoms in one ring, preferably five or six heteroatoms in each ring. It means an aromatic group which can be. Preferably the heteroaromatic group has one or two oxygen atoms, one or two sulfur atoms and / or one to four nitrogen atoms in the ring, and is bonded to the rest of the molecule via carbon or heteroatoms. Can be. Examples of heteroaromatic groups include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl and the like. Examples of substituents include hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, sia One or more substituents selected from the group consisting of furnaces, thiols, ketals, acetals, esters and ethers.
본 명세서에 단독으로 또는 다른 기의 일부분으로서 사용되는 "아실"이란 용어는 RC(O)-(여기서, R은 R1, R1O-, R1R2N- 또는 R1S이며, 여기서, R1은 히드로카르빌, 헤테로치환된 히드로카르빌 또는 헤테로시클로이고, R2는 수소, 히드로카르빌 또는 치환된 히드로카르빌임)와 같이 유기 카르복실산의 -COOH기로부터 히드록실기를 제거함으로써 형성되는 잔기를 의미한다.As used herein, alone or as part of another group, the term "acyl" is RC (O)-, wherein R is R 1 , R 1 O-, R 1 R 2 N- or R 1 S, wherein , R 1 is hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclo, and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl) and the hydroxyl group is removed from the -COOH group of the organic carboxylic acid. The residue formed by this means.
본 명세서에 단독으로 또는 다른 기의 일부분으로서 사용되는 "아실옥시"란 용어는 RC(O)O-(여기서, R은 "아실"이란 용어와 관련해 정의된 바와 같음)와 같이 산소 결합(-O-)을 통해 상기 기재된 바와 같이 결합된 아실기를 의미한다.As used herein, alone or as part of another group, the term "acyloxy" refers to an oxygen bond (-O), such as RC (O) O-, where R is as defined with respect to the term "acyl". By acyl means an acyl group bound as described above.
달리 언급하지 않는 한, 본 명세서에 기재된 알콕시카르보닐옥시 잔기는 저급 탄화수소, 치환된 탄화수소 또는 치환된 탄화수소 잔기를 포함한다.Unless stated otherwise, alkoxycarbonyloxy moieties described herein include lower hydrocarbons, substituted hydrocarbons or substituted hydrocarbon residues.
달리 언급하지 않는 한, 본 명세서에 기재된 카르바모일옥시 잔기는 1개 또는 2개의 아민 수소가 히드로카르빌, 치환된 히드로카르빌 또는 헤테로시클로 잔기에 의해 임의로 치환될 수 있는 카르밤산 유도체이다.Unless stated otherwise, carbamoyloxy moieties described herein are carbamic acid derivatives in which one or two amine hydrogens may be optionally substituted by hydrocarbyl, substituted hydrocarbyl or heterocyclo moiety.
본 명세서에 사용된 "히드록실 보호기" 및 "히드록시 보호기"란 용어는 유리 히드록실기를 보호("보호된 히드록실")할 수 있으며, 보호가 적용되는 반응 이후에 분자의 나머지 부분을 방해하지 않고 제거될 수 있는 기를 의미한다. 히드록실 기에 대한 다양한 보호기 및 이들의 합성에 대해서는 문헌[Protective Groups in Organic Synthesis, T.W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser]에서 찾아볼 수 있다. 히드록실 보호기의 예에는 메톡시메틸, 1-에톡시에틸, 벤질옥시메틸, (베타-트리메틸실릴에톡시)메틸, 테트라히드로피라닐, 2,2,2-트리클로로에톡시카르보닐, t-부틸(디페닐)실릴, 트리알킬실릴, 트리클로로메톡시카르보닐 및 2,2,2-트리클로로에톡시메틸이 포함된다.As used herein, the terms “hydroxyl protecting group” and “hydroxy protecting group” may protect (“protected hydroxyl”) free hydroxyl groups and disrupt the rest of the molecule after the reaction to which protection is applied. Means a group that can be removed without For various protective groups on hydroxyl groups and their synthesis, see Protective Groups in Organic Synthesis, T.W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Examples of hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (beta-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t- Butyl (diphenyl) silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
본 명세서에 사용된 "Ac"는 아세틸을 의미하고, "Bz"는 벤조일을 의미하고; "Et"는 에틸을 의미하고; "Me"는 메틸을 의미하고; "Ph"는 페닐을 의미하고; "iPr"은 이소프로필을 의미하고; "tBu" 및 "t-Bu"는 tert-부틸을 의미하고; "R"은 달리언급하지 않는 한 저급 알킬을 의미하고; "py"는 피리딘 또는 피리딜을 의미하고; "TES"는 트리에틸실릴을 의미하고; "TMS"는 트리메틸실릴을 의미하고; "LAH"는 수소화알루미늄리튬을 의미하고; "10-DAB"는 10-데스아세틸박카틴 Ⅲ을 의미하고; "아민 보호기"에는 2,2,2-트리클로로에틸카르바메이트 또는 tert-부틸카르바메이트와 같은 카르바메이트가 포함되지만, 이에 제한되지 않고; "보호된 히드록시"는 -OP(여기서, P는 히드록시 보호기임)를 의미하고; "PhCO"는 페닐카르보닐을 의미하고, "tBuOCO" 및 "Boc"는 tert-부톡시카르보닐을 의미하고; "tAmOCO"는 tert-아밀옥시카르보닐을 의미하고; "2-FuCO"는 2-푸릴카르보닐을 의미하고, "2-ThCO"는 2-티에닐카르보닐을 의미하고; "3-ThCO"는 3-티에닐카르보닐을 의미하고; "2-PyCO"는 2-피리딜카르보닐을 의미하고; "3-PyCO"는 3-피리딜카르보닐을 의미하고; "4-PyCO"는 4-피리딜카르보닐을 의미하고; "C4H7CO"는 부테닐카르보닐을 의미하고; "tC3H5CO"는 트랜스-프로페닐카르보닐을 의미하고; "EtOCO"는 에톡시카르보닐을 의미하고; "ibueCO"는 이소부테닐카르보닐을 의미하고; "iBuCO"는 이소부틸카르보닐을 의미하고; "iBuOCO"는 이소부톡시카르보닐을 의미하고; "iPrOCO"는 이소프로필옥시카르보닐을 의미하고; "nPrOCO"는 n-프로필옥시카르보닐을 의미하고; "nPrCO"는 n-프로필카르보닐을 의미하고; "ibue"는 이소부테닐을 의미하고; "THF"는 테트라히드로푸란을 의미하고; "DMAP"는 4-디메틸아미노 피리딘을 의미하며; "LHMDS"는 리튬 헥사메틸디실라자니드를 의미한다.As used herein, "Ac" means acetyl and "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "iPr" means isopropyl; "tBu" and "t-Bu" mean tert-butyl; "R" means lower alkyl unless stated otherwise; "py" means pyridine or pyridyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "LAH" means lithium aluminum hydride; "10-DAB" means 10-desacetylbaccatin III; "Amine protecting group" includes, but is not limited to, carbamate, such as 2,2,2-trichloroethylcarbamate or tert-butylcarbamate; "Protected hydroxy" means -OP, where P is a hydroxy protecting group; "PhCO" means phenylcarbonyl, "tBuOCO" and "Boc" mean tert-butoxycarbonyl; "tAmOCO" refers to tert-amyloxycarbonyl; "2-FuCO" means 2-furylcarbonyl and "2-ThCO" means 2-thienylcarbonyl; "3-ThCO" refers to 3-thienylcarbonyl; "2-PyCO" refers to 2-pyridylcarbonyl; "3-PyCO" refers to 3-pyridylcarbonyl; "4-PyCO" refers to 4-pyridylcarbonyl; "C 4 H 7 CO" refers to butenylcarbonyl; "tC 3 H 5 CO" refers to trans-propenylcarbonyl; "EtOCO" means ethoxycarbonyl; "ibueCO" means isobutenylcarbonyl; "iBuCO" refers to isobutylcarbonyl; "iBuOCO" refers to isobutoxycarbonyl; "iPrOCO" refers to isopropyloxycarbonyl; "nPrOCO" refers to n-propyloxycarbonyl; "nPrCO" refers to n-propylcarbonyl; "ibue" means isobutenyl; "THF" means tetrahydrofuran; "DMAP" means 4-dimethylamino pyridine; "LHMDS" means lithium hexamethyldisilazanide.
하기 실시예는 본 발명을 예시한다.The following examples illustrate the invention.
실시예 1Example 1
N-데벤조일-N-tert-아밀옥시카르보닐-3'-데스페닐-3'-(2-푸릴)-10-데아세틸-7-메톡시아세틸 탁솔 (6226)N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3 '-(2-furyl) -10-deacetyl-7-methoxyacetyl taxol (6226)
에틸 아세테이트 50 ㎖ 중의 N-데벤조일-N-tert-아밀옥시카르보닐-3'-데스페닐-3'-(2-푸릴)-2'-(2-메톡시-2-프로필)-7-벤조일옥시카르보닐-10-데아세틸-10-트리메틸실릴 탁솔(2.05 g, 2.292 m㏖)의 용액에 10% Pd-C (500 ㎎)을 가하고, 혼합물을 수소 대기하(라텍스 풍선) 주변 온도에서 45분 동안 교반하였다. 반응물을 TLC(실리카 겔, 1:1 에틸 아세테이트:헥산)한 결과, 생성물만 존재한다는 것을 나타내었다. 그 후, 혼합물을 셀라이트 베드(5 g)를 통해 여과하고, 셀라이트를 에틸 아세테이트 25 ㎖로 세척하였다. 에틸 아세테이트 분획을 합하고, 감압하에 농축시켜 N-데벤조일-N-tert-아밀옥시카르보닐-3'-데스페닐-3'-(2-푸릴)-2'-(2-메톡시-2-프로필)-10-데아세틸-10-트리메틸실릴 탁솔을 백색 고체로서 2.10 g(96%)를 얻었으며, 이를 다음 단계에 직접 사용하였다.N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3 '-(2-furyl) -2'-(2-methoxy-2-propyl) -7- in 50 ml of ethyl acetate To a solution of benzoyloxycarbonyl-10-deacetyl-10-trimethylsilyl taxol (2.05 g, 2.292 mmol) is added 10% Pd-C (500 mg) and the mixture is brought to hydrogen atmosphere (latex balloon) at ambient temperature. Stir for 45 minutes. TLC (silica gel, 1: 1 ethyl acetate: hexane) of the reaction showed that only the product was present. The mixture was then filtered through a celite bed (5 g) and the celite was washed with 25 ml of ethyl acetate. The ethyl acetate fractions were combined and concentrated under reduced pressure to yield N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3 '-(2-furyl) -2'-(2-methoxy-2- Propyl) -10-deacetyl-10-trimethylsilyl taxol was obtained as a white solid of 2.10 g (96%), which was used directly in the next step.
0℃의 무수 피리딘 4 ㎖ 중의 N-데벤조일-N-tert-아밀옥시카르보닐-3'-데스페닐-3'-(2-푸릴)-2'-(2-메톡시-2-프로필)-10-데아세틸-10-트리메틸실릴 탁솔(400 ㎎, 0.418 m㏖)의 용액에 DMAP(20 ㎎, 0.16 m㏖)를 질소 대기하에서 가하였다. 상기 혼합물에 메톡시아세틸 클로라이드(96 ㎖, 1.045 m㏖)를 적가하였다. 3시간 후, TLC(실리카 겔, 2:3 에틸 아세테이트:헥산)는 출발 물질이 존재하지 않는다는 것을 나타내었다. 반응물을 (빙수조에서) 0℃로 냉각시키고, 물 80 ㎖를 가하여 반응을 정지시켰다.N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3 '-(2-furyl) -2'-(2-methoxy-2-propyl) in 4 ml of anhydrous pyridine at 0 ° C. DMAP (20 mg, 0.16 mmol) was added to a solution of -10-deacetyl-10-trimethylsilyl taxol (400 mg, 0.418 mmol) under a nitrogen atmosphere. To the mixture was added dropwise methoxyacetyl chloride (96 mL, 1.045 mmol). After 3 hours, TLC (silica gel, 2: 3 ethyl acetate: hexane) showed no starting material present. The reaction was cooled to 0 ° C. (in an ice bath) and 80 ml of water was added to stop the reaction.
0℃(빙수조)의 반응물에 아세토니트릴 4 ㎖ 및 48% 수성 플루오르화수소산 2 ㎖를 가하고, 냉각조를 제거하였다. 반응물을 실온에서 8.0시간 동안 교반한 후, 에틸 아세테이트 60 ㎖로 희석시키고, 포화 수성 NaHCO32×10 ㎖로 세척한 후, 포화 수성 NaCl 15 ㎖로 세척하였다. 유기층을 황산나트륨으로 건조시키고, 감압하에 농축시켜 황색 고체 365 ㎎을 얻었으며, 이를 플래시 크로마토그래피 (실리카 겔, 1:1 에틸 아세테이트:헥산)로 정제하여 N-데벤조일-N-tert-아밀옥시카르보닐-3'-데스페닐-3'-(2-푸릴)-10-데아세틸-7-메톡시아세틸 탁솔 325 ㎎(88%)을 얻었다.4 ml of acetonitrile and 2 ml of 48% aqueous hydrofluoric acid were added to the reaction at 0 ° C. (ice water bath), and the cooling bath was removed. The reaction was stirred at room temperature for 8.0 hours, then diluted with 60 ml of ethyl acetate, washed with 2 x 10 ml of saturated aqueous NaHCO 3 and then with 15 ml of saturated aqueous NaCl. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 365 mg of a yellow solid, which was purified by flash chromatography (silica gel, 1: 1 ethyl acetate: hexane) to give N-debenzoyl-N-tert-amyloxycarbine. 325 mg (88%) of carbonyl-3'-desphenyl-3 '-(2-furyl) -10-deacetyl-7-methoxyacetyl taxol were obtained.
실시예 2Example 2
실시예 1에서 기술한 절차를 반복하였지만, 실시예 1의 β-락탐을 다른 적합한 보호된 β-락탐으로 치환하여 하기 화학식 13 및 하기 표에 정의된 치환체의 조합을 갖는 일련의 화합물을 제조하였다.Although the procedure described in Example 1 was repeated, the β-lactam of Example 1 was substituted with another suitable protected β-lactam to prepare a series of compounds having a combination of substituents as defined in Formula 13 below and in the table below.
실시예 3Example 3
본 명세서의 여타 부분에서 기술된 방법에 따라, R7은 상기 정의된 바이고, 식 중에서 R7이 R7aCOO-이고, R7a는 헤테로치환된 메틸인 것을 포함하는 하기 화학식 1를 갖는 다음의 특정 탁산을 제조할 수 있다. 한 실시양태에서, R7a는 클로로메틸, 히드록시메틸, 메톡시메틸, 에톡시메틸, 페녹시메틸, 아세톡시메틸 또는 메틸티오메틸이다.According to the methods described elsewhere herein, R 7 is defined above and wherein R 7 is R 7a COO—, wherein R 7a is heterosubstituted methyl, with the following specific formula (1) Taxanes can be prepared. In one embodiment, R 7a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl or methylthiomethyl.
실시예 4Example 4
실시예 1 및 본 명세서의 여타 부분에 기술된 방법에 따라서, R10은 히드록시이고, 각 계열 (즉, 계열 "A" 내지 "K")에서의 R7은 상기 정의한 바와 같으며, 식 중에서 R7이 R7aCOO-이고, R7a는 R7a를 치환체로 갖는 탄소에 대해 베타 위치에 있는 탄소를 함유하지 않는 헤테로치환된 메틸 잔기인 것을 포함하는 하기 화학식 15의 구조를 갖는 다음의 특정 탁산을 제조할 수 있다. 헤테로치환된 메틸은 1개 이상의 헤테로원자(예를 들면, 질소, 산소, 규소, 인, 붕소, 황 또는 할로겐 원자임)및 임의로는 수소와 공유결합되어 있다. 또한, 헤테로원자는 다른 원자로 치환되어 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 옥시, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 또는 에테르 잔기를 형성할 수 있다. R7치환체의 예로는 R7aCOO-가 있으며, 여기서 R7a는 수소, 메틸, 클로로메틸, 히드록시메틸, 메톡시메틸, 에톡시메틸, 페녹시메틸, 아세톡시메틸, 아실옥시메틸 또는 메틸티오메틸이다.Example 1 and was prepared according to the procedure described in other portions of this specification, R 10 is hydroxy, each series (that is, the series "A" through "K") R 7 in are as defined above, of the formula The following specific taxanes having the structure of Formula 15 wherein R 7 is R 7a COO— and R 7a is a heterosubstituted methyl moiety that does not contain a carbon at the beta position relative to carbon having R 7a as a substituent; Can be prepared. Heterosubstituted methyl is covalently bonded with one or more heteroatoms (eg, nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms) and optionally hydrogen. In addition, heteroatoms are substituted with other atoms such as heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester Or ether residues. Examples of R 7 substituents are R 7a COO—, where R 7a is hydrogen, methyl, chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl or methylthio Methyl.
"A" 계열 화합물에서, X10은 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이며, R7및 R10각각은 베타 입체이성질체 배위를 가진다.In the "A" series compounds, X 10 is as defined elsewhere herein. Preferably, heterocyclo is substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert- Butyl) and each of R 7 and R 10 has a beta stereoisomer configuration.
"B" 계열 화합물에서, X10및 R2a는 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이고, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7및 R10각각은 베타 입체이성질체 배위를 가진다.In the "B" family of compounds, X 10 and R 2a are as defined elsewhere herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, and each of R 7 and R 10 has a beta stereoisomeric configuration.
"C" 계열 화합물에서, X10및 R9a는 본 명세서에서 달리 정의한 바와 같다.바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이고, R9a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7, R9및 R10각각은 베타 입체이성질체 배위를 가진다.In the “C” family compounds, X 10 and R 9a are as defined elsewhere herein. Preferably, the heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl, and X 10 is preferred. Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg tert-butyl), R 9a is preferably substituted or unsubstituted furyl, thienyl, pyridyl , Phenyl or lower alkyl, each of R 7 , R 9 and R 10 has a beta stereoisomer configuration.
"D" 및 "E" 계열 화합물에서, X10은 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이며, R7, R9(계열 D에서만) 및 R10각각은 베타 입체이성질체 배위를 가진다.In the "D" and "E" family compounds, X 10 is as defined elsewhere herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), for example, R 7 , R 9 (series D only) and R 10 each have a beta stereoisomeric configuration.
"F" 계열 화합물에서, X10, R2a및 R9a는 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이며, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7, R9및 R10각각은 베타 입체이성질체 배위를 가진다.In the "F" family of compounds, X 10 , R 2a and R 9a are as defined elsewhere herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R 7 , R 9 and R 10 is a beta stereoisomer configuration Has
"G" 계열 화합물에서, X10및 R2a는 본 명세서에서 달리 정의한 바와 같다.바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이며, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급알킬이며, R7, R9및 R10각각은 베타 입체이성질체 배위를 가진다.In the "G" family compounds, X 10 and R 2a are as defined elsewhere herein. Preferably, the heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl, and X 10 is preferred. Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl , Phenyl or lower alkyl, each of R 7 , R 9 and R 10 has a beta stereoisomer configuration.
"H" 계열 화합물에서, X10은 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이며, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7및 R10각각은 베타 입체이성질체 배위를 가진다.In the "H" family of compounds, X 10 is as otherwise defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R 7 and R 10 has a beta stereoisomeric configuration.
"I" 계열 화합물에서, X10및 R2a는 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이고, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7및 R10각각은 베타 입체이성질체 배위를 가진다.In the "I" series compounds, X 10 and R 2a are as defined elsewhere herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, and each of R 7 and R 10 has a beta stereoisomeric configuration.
"J" 계열 화합물에서, X10및 R2a는 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이고, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7, R9및 R10각각은 베타 입체이성질체 배위를 가진다.In the "J" family of compounds, X 10 and R 2a are as defined elsewhere herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R 7 , R 9 and R 10 is a beta stereoisomer configuration Has
"K" 계열 화합물에서, X10, R2a및 R9a는 본 명세서에서 달리 정의한 바와 같다. 바람직하게는, 헤테로시클로는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐 또는 피리딜이고, X10은 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬 (예를 들면, tert-부틸)이고, R2a는 바람직하게는 치환된 또는 비치환된 푸릴, 티에닐, 피리딜, 페닐 또는 저급 알킬이며, R7, R9및 R10각각은 베타 입체이성질체 배위를 가진다.In the "K" family compounds, X 10 , R 2a and R 9a are as defined elsewhere herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X 10 is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl ( Tert-butyl), R 2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R 7 , R 9 and R 10 is a beta stereoisomer configuration Has
X3, X5, R2, R7및 R9각각의 임의의 치환체는 히드로카르빌 또는 헤테로시클로, 알콕시, 알켄옥시, 알킨옥시, 아릴옥시, 히드록시, 보호된 히드록시, 케토, 아실옥시, 니트로, 아미노, 아미도, 티올, 케탈, 아세탈, 에스테르 및 에테르 잔기로 구성된 군으로부터 선택되지만, 인 함유 잔기는 아닌 임의의 헤테로원자 함유 치환체일 수 있다.Optional substituents of each of X 3 , X 5 , R 2 , R 7 and R 9 are hydrocarbyl or heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy And any heteroatom containing substituents selected from the group consisting of nitro, amino, amido, thiol, ketal, acetal, ester and ether residues, but not phosphorus containing residues.
실시예 5Example 5
시험관내 세포 집락 형성능 검정에 의해 측정한 세포독성Cytotoxicity As Determined by In Vitro Cell Colony Formation Assay
4백개의 HCT116 세포를 2.7 ㎖의 배지 (10% 소 태아 혈청 및 100 유닛/㎖ 페니실린 및 100 g/㎖ 스트렙토마이신을 함유하는 개질 맥코이(McCoy's) 5a 배지)를 함유하는 60 ㎜ 페트리 접시에 플레이트하였다. 세포를 페트리 접시 바닥에 부착되도록 하기 위해서 37℃에서 5시간 동안 CO2배양기에서 배양하였다. 실시예 2에서 확인된 화합물들을 배지중에 최종 농도의 10배로 신선하게 제조하고, 이어서 이 원액 0.3 ㎖을 접시의 2.7 ㎖ 배지에 가하였다. 이어서, 세포를 약물과 함께 72시간 동안 37℃에서 배양하였다. 배양 종결시 약물 함유 배지를 조심스럽게 따라내고, 4 ㎖의 행크스 발란스 염 용액 (Hank's Balance Salt Solution, HBSS)으로 접시를 세척하였고, 5 ㎖의 새로운 배지를 가하였으며, 접시를 집락 형성을 위해 배양기로 다시 옮겼다. 7일간 배양한 후 세포 집락을 집락 계수기를 사용하여 세었다. 세포 생존률을 계산하였고, 각 시험 화합물에 대해 ID50 (집락 형성을 50%억제하는 약물 농도) 값을 결정하였다.Four hundred HCT116 cells were plated in a 60 mm Petri dish containing 2.7 ml of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units / ml penicillin and 100 g / ml streptomycin). . Cells were incubated in a CO 2 incubator at 37 ° C. for 5 hours to allow for attachment to the Petri dish bottom. The compounds identified in Example 2 were freshly prepared at 10 times the final concentration in the medium, and 0.3 ml of this stock solution was then added to the 2.7 ml medium of the dish. Cells were then incubated at 37 ° C. for 72 hours with drug. At the end of the incubation, the drug containing medium was carefully decanted, the dishes were washed with 4 ml Hanks Balance Salt Solution (HBSS), 5 ml fresh medium was added, and the plates were transferred to the incubator to form colonies. Moved again. After 7 days of incubation, cell colonies were counted using a colony counter. Cell viability was calculated and ID50 (drug concentration inhibiting 50% colony formation) values were determined for each test compound.
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2001
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EP1200424A1 (en) | 2002-05-02 |
ATE413397T1 (en) | 2008-11-15 |
NZ514411A (en) | 2005-02-25 |
EP1200424B1 (en) | 2008-11-05 |
US7183312B2 (en) | 2007-02-27 |
HK1047935A1 (en) | 2003-03-14 |
PL350328A1 (en) | 2002-12-02 |
BR0104353A (en) | 2002-04-16 |
CA2368534A1 (en) | 2001-08-09 |
MXPA01009922A (en) | 2003-07-14 |
NO20014758D0 (en) | 2001-10-01 |
US20050143446A1 (en) | 2005-06-30 |
US20040087547A1 (en) | 2004-05-06 |
ZA200108063B (en) | 2003-12-01 |
CZ20013519A3 (en) | 2002-04-17 |
US6673833B2 (en) | 2004-01-06 |
IL145642A0 (en) | 2002-06-30 |
WO2001057029A1 (en) | 2001-08-09 |
AU3480401A (en) | 2001-08-14 |
HUP0200651A2 (en) | 2002-07-29 |
AU776765B2 (en) | 2004-09-23 |
JP2003522169A (en) | 2003-07-22 |
NO20014758L (en) | 2001-11-29 |
HUP0200651A3 (en) | 2002-10-28 |
US6861446B2 (en) | 2005-03-01 |
US20020065305A1 (en) | 2002-05-30 |
CN1362957A (en) | 2002-08-07 |
DE60136430D1 (en) | 2008-12-18 |
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